Inhibitors of Iap

ABSTRACT

Novel compounds that inhibit the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs) of the formula I

The present invention relates generally to novel compounds that inhibitthe binding of the Smac protein to Inhibitor of Apoptosis Proteins(IAPs). The present invention includes novel compounds, novelcompositions, methods of their use and methods of their manufacture,where such compounds are generally pharmacologically useful as agents intherapies whose mechanism of action rely on the inhibition of theSmac/IAP interaction, and more particularly useful in therapies for thetreatment of proliferative diseases, including cancer.

BACKGROUND

Programmed cell death plays a critical role in regulating cell numberand in eliminating stressed or damaged cells from normal tissues.Indeed, the network of apoptotic signaling mechanisms inherent in mostcell types provides a major barrier to the development and progressionof human cancer. Since most commonly used radiation and chemo-therapiesrely on activation of apoptotic pathways to kill cancer cells, tumorcells which are capable of evading programmed cell death often becomeresistant to treatment.

Apoptosis signaling networks are classified as either intrinsic whenmediated by death receptor-ligand interactions or extrinsic whenmediated by cellular stress and mitochondrial permeabilization. Bothpathways ultimately converge on individual Caspases. Once activated,Caspases cleave a number of cell death-related substrates, effectingdestruction of the cell.

Tumor cells have devised a number of strategies to circumvent apoptosis.One recently reported molecular mechanism involves the overexpression ofmembers of the IAP (Inhibitor of Apoptosis) protein family. IAPssabotage apoptosis by directly interacting with and neutralizingCaspases. The prototype IAPs, XIAP and cIAP have three functionaldomains referred to as BIR 1, 2 & 3 domains. BIR3 domain interactsdirectly with Caspase 9 and inhibits its ability to bind and cleave itsnatural substrate, Procaspase 3.

It has been reported that a proapoptotic mitochondrial protein, Smac(also known as DIABLO), is capable of neutralizing XIAP and/or cIAP bybinding to a peptide binding pocket (Smac binding site) on the surfaceof BIR3 thereby precluding interaction between XIAP and/or cIAP andCaspase 9. The present invention relates to therapeutic molecules thatbind to the Smac binding pocket thereby promoting apoptosis in rapidlydividing cells. Such therapeutic molecules are useful for the treatmentof proliferative diseases, including cancer. In other words, Smacanalogs would bind to BIR3 domain of IAPs and will remove the IAP'sinhibition of activated Caspase 9 which would then go on to induceapoptosis.

SUMMARY OF THE INVENTION

The present invention relates generally to novel compounds that inhibitthe binding of the Smac protein to Inhibitor of Apoptosis Proteins(IAPs). The present invention includes novel compounds, novelcompositions, methods of their use and methods of their manufacture,where such compounds are generally pharmacologically useful as agents intherapies whose mechanism of action rely on the inhibition of theSmac/IAP interaction, and more particularly useful in therapies for thetreatment of proliferative diseases, including cancer.

DETAILED DESCRIPTION

The present invention relates to compounds of the formula (I)

whereinR₁ is H; C₁-C₄ alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl or C₃-C₁₀cycloalkylwhich are unsubstituted or substituted;R₂ is H; C₁-C₄ alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl or C₃-C₁₀cycloalkylwhich are unsubstituted or substituted;R₃ is H; —CF₃; —C₂F₅; C₁-C₄ alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl; —CH₂-Zor R₂ and R₃ together with the nitrogen form a het ring;

Z is H; —OH; F; Cl; —CH₃; —CF₃; —CH₂Cl; —CH₂F or —CH₂OH;

R₄ is C₁-C₁₆ straight or branched alkyl; C₁-C₁₆ alkenyl; C₁-C₁₆ alkynyl;or —C₃-C₁₀cycloalkyl; —(CH₂)₁₋₆-Z₁; —(CH₂)₀₋₆-aryl; and —(CH₂)₀₋₆-het;wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;Z₁ is —N(R₈)—C(O)—C₁-C₁₀alkyl; —N(R₈)—C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—N(R₈)—C(O)—(CH₂)₀₋₆-phenyl; —N(R₈)—C(O)—(CH₂)₁₋₆-het; —C(O)—N(R₉)(R₁₀);—C(O)—O—C₁-C₁₀alkyl; —C(O)—O—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—C(O)—O—(CH₂)₀₋₆-phenyl; —C(O)—O—(CH₂)₁₋₆-het; —O—C(O)—C₁-C₁₀alkyl;—O—C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —O—C(O)—(CH₂)₀₋₆-phenyl;—O—C(O)—(CH₂)₁₋₆-het; wherein alkyl, cycloalkyl and phenyl areunsubstituted or substituted;het is a 5-7 membered heterocyclic ring containing 1-4 heteroatomsselected from N, O and S, or an 8-12 membered fused ring systemincluding at least one 5-7 membered heterocyclic ring containing 1, 2 or3 heteroatoms selected from N, O, and S, which heterocyclic ring orfused ring system is unsubstituted or substituted on a carbon ornitrogen atom;

R₈ is H; —CH₃; —CF₃; —CH₂OH or —CH₂Cl;

R₉ and R₁₀ are each independently H; C₁-C₄alkyl; C₃-C₇cycloalkyl;—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —(CH₂)₀₋₆-phenyl; wherein alkyl, cycloalkyland phenyl are unsubstituted or substituted, or R₉ and R₁₀ together withthe nitrogen form het;R₅ is H; C₁-C₁₀-alkyl; aryl; phenyl; C₃-C₇cycloalkyl;—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —C₁-C₁₀alkyl-aryl;—(CH₂)₀₋₆—C₃-C₇cycloalkyl-(CH₂)₀₋₆-phenyl;—(CH₂)₀₋₄CH—((CH₂)₁₋₄-phenyl)₂; —(CH₂)₀₋₆—CH(phenyl)₂; -indanyl;—C(O)—C₁-C₁₀alkyl; —C(O)—(CH₂)₁₋₆—C₃-C₇-cycloalkyl;—C(O)—(CH₂)₀₋₆-phenyl; —(CH₂)₀₋₆—C(O)-phenyl; —(CH₂)₀₋₆-het;—C(O)—(CH₂)₁₋₆-het; or R₅ is a residue of an amino acid, wherein thealkyl, cycloalkyl, phenyl and aryl substituents are unsubstituted orsubstituted;U is as shown in structure II:

whereinn=0-5;

X is —CH or N;

Ra and Rb are independently an O, S, or N atom or C₀₋₈ alkyl wherein oneor more of the carbon atoms in the alkyl chain may be replaced by aheteroatom selected from O, S or N, and where the alkyl may beunsubstituted or substituted;Rd is selected from:

-   -   (a) —Re-Q-(Rf)_(p)(Rg)_(q); or    -   (b) Ar₁-D-Ar₂;        Rc is H or Rc and Rd may together form a cycloalkyl or het;        where if Rd and Rc form a cycloalkyl or het, R₅ is attached to        the formed ring at a C or N atom;        p and q are independently 0 or 1;        Re is C₁₋₈ alkyl or alkylidene, and Re which may be        unsubstituted or substituted;

Q is N, O, S, S(O), or S(O)₂;

Ar₁ and Ar₂ are substituted or unsubstituted aryl or het;Rf and Rg are each independently H; —C₁-C₁₀alkyl; C₁-C₁₀alkylaryl; —OH;—O—C₁-C₁₀alkyl; —(CH₂)₀₋₆—C₃-C₇cycloalkyl; —O—(CH₂)₀₋₆-aryl; phenyl;aryl; phenyl-phenyl; —(CH₂)₁₋₆-het; —O—(CH₂)₁₋₆-het; —OR₁₁; —C(O)—R₁₁;—C(O)—N(R₁₁)(R₁₂); —N(R₁₁)(R₁₂); —S—R₁₁; —S(O)—R₁₁; —S(O)₂—R₁₁;—S(O)₂—NR₁₁R₁₂; —NR₁₁—S(O)₂—R₁₂; S—C₁-C₁₀alkyl; aryl-C₁-C₄alkyl;het-C₁-C₄-alkyl wherein alkyl, cycloalkyl, het and aryl areunsubstituted or substituted; —SO₂—C₁-C₂alkyl; —SO₂—C₁-C₂alkylphenyl;—O—C₁-C₄alkyl; or R_(g) and R_(f) form a ring selected from het or aryl;D is —CO—; —C(O)—C₁₋₇ alkylene or arylene; —CF₂—; —O—; —S(O)_(r) where ris 0-2; 1,3dioaxolane; or C₁₋₇ alkyl-OH; where alkyl, alkylene orarylene may be unsubstituted or substituted with one or more halogens,OH, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃; or D is —N(Rh) wherein Rh isH; C₁₋₇ alkyl (unsub or substituted); aryl; —O(C₁₋₇cycloalkyl) (unsub orsubstituted); C(O)—C₁-C₁₀alkyl; C(O)—C_(o)—C₁₀alkylaryl;C—O—C₁-C₁₀alkyl; C—O—C_(o)—C₁₀alkyl-aryl or SO₂—C₁-C₁₀-alkyl;SO₂—(C_(o)—C₁₀-alkylaryl);R₆, R₇, R′₆ and R′₇ are each independently H; —C₁-C₁₀ alkyl; —C₁-C₁₀alkoxy; aryl-C₁-C₁₀ alkoxy; —OH; —O—C₁-C₁₀alkyl;—(CH₂)₀₋₆—C₃-C₇cycloalkyl; —O—(CH₂)₀₋₆-aryl; phenyl; —(CH₂)₁₋₆-het;—O—(CH₂)₁₋₆-het; —OR₁₁; —C(O)—R₁₁; —C(O)—N(R₁₁)(R₁₂); —N(R₁₁)(R₁₂);—S—R₁₁; —S(O)—R₁₁; —S(O)₂—R₁₁; —S(O)₂—NR₁₁R₁₂; —NR₁₁—S(O)₂—R₁₂; whereinalkyl, cycloalkyl and aryl are unsubstituted or substituted; and R₆, R₇,R′₆ and R′₇ can be united to form a ring system;R₁₁ and R₁₂ are independently H; C₁-C₁₀ alkyl;—(CH₂)₀₋₆—C₃-C₇cycloalkyl; —(CH₂)₀₋₆—(CH)₀₋₁(aryl)₁₋₂;—C(O)—C₁-C₁₀alkyl; —C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—C(O)—O—(CH₂)₀₋₆-aryl; —C(O)—(CH₂)₀₋₆—O-fluorenyl;—C(O)—NH—(CH₂)₀₋₆-aryl; —C(O)—(CH₂)₀₋₆-aryl; —C(O)—(CH₂)₁₋₆-het;—C(S)—C₁-C₁₀alkyl; —C(S)—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—C(S)—O—(CH₂)₀₋₆-aryl; —C(S)—(CH₂)₀₋₆—O-fluorenyl;—C(S)—NH—(CH₂)₀₋₆-aryl; —C(S)—(CH₂)₀₋₆-aryl; —C(S)—(CH₂)₁₋₆-het; whereinalkyl, cycloalkyl and aryl are unsubstituted or substituted; or R₁₁ andR₁₂ are a substituent that facilitates transport of the molecule acrossa cell membrane; or R₁₁ and R₁₂ together with the nitrogen atom formhet;wherein the alkyl substituents of R₁₁ and R₁₂ may be unsubstituted orsubstituted by one or more substituents selected from C₁-C₁₀alkyl,halogen, OH, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃;substituted cycloalkyl substituents of R₁₁ and R₁₂ are substituted byone or more substituents selected from a C₁-C₁₀ alkene; C₁-C₆alkyl;halogen; OH; —O—C₁-C₆alkyl; —S—C₁-C₆alkyl or —CF₃; andsubstituted phenyl or aryl of R₁₁ and R₁₂ are substituted by one or moresubstituents selected from halogen; hydroxy; C₁-C₄ alkyl; C₁-C₄ alkoxy;nitro; —CN; —O—C(O)—C₁-C₄alkyl and —C(O)—O—C₁-C₄-aryl,or pharmaceutically acceptable salts thereof.

The present invention also related to the use of compound of formula Iin the treatment of proliferative diseases, especially those dependenton the binding of the Smac protein to Inhibitor of Apoptosis Proteins(IAPs), or for the manufacture of pharmaceutical compositions for use inthe treatment of said diseases, methods of use of compounds of formula(I) in the treatment of said diseases, pharmaceutical preparationscomprising compounds of formula (I) for the treatment of said diseases,compounds of formula (I) for use in the treatment of said diseases.

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated:

“Aryl” is an aromatic radical having 6 to 14 carbon atoms, which may befused or unfused, and which is unsubstituted or substituted by one ormore, preferably one or two substituents, wherein the substituents areas described below. Preferred “aryl” is phenyl, naphthyl or indanyl.

“Het” refers to heteroaryl and heterocyclic rings and fused ringscontaining aromatic and non-aromatic heterocyclic rings. “Het” is a 5-7membered heterocyclic ring containing 1-4 heteroatoms selected from N, Oand S, or an 8-12 membered fused ring system including at least one 5-7membered heterocyclic ring containing 1, 2 or 3 heteroatoms selectedfrom N, O, and S. Suitable het substituents include unsubstituted andsubstituted pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl,piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane,1,4-diazapane, 1,4-oxazepane, 1,4-oxathiapane, furyl, thienyl, pyrrole,pyrazole, triazole, 1,2,3-triazole, tetrazolyl, oxadiazole, thiophene,imidazol, pyrrolidine, pyrrolidone, thiazole, oxazole, pyridine,pyrimidine, isoxazolyl, pyrazine, quinoline, isoquinoline,pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran,benzothiofuran, benzindole, benzoxazole, pyrroloquinoline, and the like.The het substituents are unsubstituted or substituted on a carbon atomby halogen, especially fluorine or chlorine, hydroxy, C₁-C₄ alkyl, suchas methyl and ethyl, C₁-C₄ alkoxy, especially methoxy and ethoxy, nitro,—O—C(O)—C₁-C₄alkyl or —C(O)—O—C₁-C₄alkyl or on a nitrogen by C₁-C₄alkyl, especially methyl or ethyl, —O—C(O)—C₁-C₄alkyl or—C(O)—O—C₁-C₄alkyl, such as carbomethoxy or carboethoxy.

When two substituents together with a commonly bound nitrogen are het,it is understood that the resulting heterocyclic ring is anitrogen-containing ring, such as aziridine, azetidine, azole,piperidine, piperazine, morphiline, pyrrole, pyrazole, thiazole,oxazole, pyridine, pyrimidine, isoxazolyl, and the like.

Halogen is fluorine, chlorine, bromine or iodine, especially fluorineand chlorine.

Unless otherwise specified “alkyl” includes straight or branched chainalkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, n-pentyl and branched pentyl, n-hexyl and branched hexyl,and the like.

A “cycloalkyl” group means C₃ to C₁₀cycloalkyl having 3 to 8 ring carbonatoms and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl. Preferably, cycloalkyl iscycloheptyl. The cycloalkyl group may be unsubstituted or substitutedwith any of the substituents defined below, preferably halo, hydroxy orC₁-C₄ alkyl such as methyl.

The amino acid residues include a residue of a standard amino acid, suchas alanine, arginine, asparagine, aspartic acid, cysteine, glutamine,glutamic acid, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine and valine. The amino acid residues also include the sidechains of uncommon and modified amino acids. Uncommon and modified aminoacids are known to those of skill in the art (see for example G. B.Fields, Z. Tiam and G Barany; Synthetic Peptides A Users Guide,University of Wisconsin Biochemistry Center, Chapter 3, (1992)) andinclude amino acids such as 4-hydroxyproline, 5-hydroxylysine,desmosine, beta-alanine, alpha, gamma- and beta-aminobutric acid,homocysteine, homoserine, citrulline, ornithine, 2- or 3-amino adipicacid, 6-aminocaproic acid, 2- or 3-aminoisobutric acid,2,3-diaminopropionic acid, diphenylalanine, hydroxyproline and the like.If the side chain of the amino acid residue contains a derivatizablegroup, such as COOH, —OH or amino, the side chain may be derivatized bya substituent that reacts with the derivatizable group. For example,acidic amino acids, like aspartic and glutamic acid, or hydroxysubstituted side chains, like those of serine or threonine, may bederivatized to form an ester, or amino side chains may form amide oralkylamino derivatives. In particular, the derivative may be asubstituent that facilitates transport across a cell membrane. Inaddition, any carboxylic acid group in the amino acid residue, forexample, an alpha carboxylic acid group, may be derivatized as discussedabove to form an ester or amide.

Substituents that facilitate transport of the molecule across a cellmembrane are known to those of skill in the medicinal chemistry arts(see, for example, Gangewar S., Pauletti G. M., Wang B., Siahaan T. J.,Stella V. J., Borchardt R. T., Drug Discovery Today, vol. 2. p 148-155(1997) and Bundgaard H. and Moss J., Pharmaceutical Research, vol. 7, p885 (1990)). Generally, such substituents are lipophillic substituents.Such lipophillic substituents include a C₆-C₃₀ alkyl which is saturated,monounsaturated, polyunsaturated, including methylene-interruptedpolyene, phenyl, phenyl which substituted by one or two C₁-C₈ alkylgroups, C₅-C₉ cycloalkyl, C₅-C₉ cycloalkyl which is substituted by oneor two C₁-C₈ alkyl groups, —X₁-phenyl, —X₁-phenyl which is substitutedin the phenyl ring by one or two C₁-C₈ alkyl groups, X₁—C₅-C₉ cycloalkylor X₁—C₅-C₉ cycloalkyl which is substituted by one or two C₁-C₈ alkylgroups; where X₁ is C₁-C₂₄ alkyl which is saturated, monounsaturated orpolyunsaturated and straight or branched chain.

Unsubstituted is intended to mean that hydrogen is the only substituent.

Any of the above defined aryl, het, alkyl, cycloalkyl, or heterocyclicgroups may be unsubstituted or independently substituted by up to four,preferably one, two or three substituents, selected from the groupconsisting of: halo (such as Cl or Br); hydroxy; lower alkyl (such asC₁-C₃ lower alkyl); lower alkyl which may be substituted with any of thesubstituents defined herein; lower alkenyl; lower alkynyl; loweralkanoyl; alkoxy (such as methoxy); aryl (such as phenyl or benzyl);substituted aryl (such as fluoro phenyl or methoxy phenyl); amino; mono-or disubstituted amino; amino lower alkyl (such as dimethylamino);acetyl amino; amino lower alkoxy (such as ethoxyamine); nitro; cyano;cyano lower alkyl; carboxy; esterified carboxy (such as lower alkoxycarbonyl e.g. methoxy carbonyl); n-propoxy carbonyl or iso-propoxycarbonyl; alkanoyl; benzoyl; carbamoyl; N-mono- or N,N-disubstitutedcarbamoyl; carbamates; alkyl carbamic acid esters; amidino; guanidine;urea; ureido; mercapto; sulfo; lower alkylthio; sulfoamino; sulfonamide;benzosulfonamide; sulfonate; sulfanyl lower alkyl (such as methylsulfanyl); sulfoamino; substituted or unsubstituted sulfonamide (such asbenzo sulfonamide); substituted or unsubstituted sulfonate (such aschloro-phenyl sulfonate); lower alkylsulfinyl; phenylsulfinyl;phenyl-lower alkylsulfinyl; alkylphenylsulfinyl; lower alkanesulfonyl;phenylsulfonyl; phenyl-lower alkylsulfonyl; alkylphenylsulfonyl;halogen-lower alkylmercapto; halogen-lower alkylsulfonyl; such asespecially trifluoromethane sulfonyl; phosphono (—P(═O)(OH)₂);hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl;substituted urea (such as 3-trifluoro-methyl-phenyl urea); alkylcarbamic acid ester or carbamates (such as ethyl-N-phenyl-carbamate) or—NR₄R₅, wherein R₄ and R₅ can be the same or different and areindependently H; lower alkyl (e.g. methyl, ethyl or propyl); or R₄ andR₅ together with the N atom form a 3- to 8-membered heterocyclic ringcontaining 1-4 nitrogen, oxygen or sulfur atoms (e.g. piperazinyl,pyrazinyl, lower alkyl-piperazinyl, pyridyl, indolyl, thiophenyl,thiazolyl, n-methyl piperazinyl, benzothiophenyl, pyrrolidinyl,piperidino or imidazolinyl) where the heterocyclic ring may besubstituted with any of the substituents defined herein.

Preferably the above mentioned alkyl, cycloalkyl, aryl or het groups maybe substituted by halogen, carbonyl, thiol, S(O), S(O₂), —OH, —SH,—OCH₃, —SCH₃, —CN, —SCN or nitro.

Where the plural form is used for compounds, salts, pharmaceuticalpreparations, diseases and the like, this is intended to mean also asingle compound, salt, or the like.

It will be apparent to one of skill in the art when a compound of theinvention can exist as a salt form, especially as an acid addition saltor a base addition salt. When a compound can exist in a salt form, suchsalt forms are included within the scope of the invention. Although anysalt form may be useful in chemical manipulations, such as purificationprocedures, only pharmaceutically acceptable salts are useful forpharmaceutically products.

Pharmaceutically acceptable salts include, when appropriate,pharmaceutically acceptable base addition salts and acid addition salts,for example, metal salts, such as alkali and alkaline earth metal salts,ammonium salts, organic amine addition salts, and amino acid additionsalts, and sulfonate salts. Acid addition salts include inorganic acidaddition salts such as hydrochloride, sulfate and phosphate, and organicacid addition salts such as alkyl sulfonate, arylsulfonate, acetate,maleate, fumarate, tartrate, citrate and lactate. Examples of metalsalts are alkali metal salts, such as lithium salt, sodium salt andpotassium salt, alkaline earth metal salts such as magnesium salt andcalcium salt, aluminum salt, and zinc salt. Examples of ammonium saltsare ammonium salt and tetramethylammonium salt. Examples of organicamine addition salts are salts with morpholine and piperidine. Examplesof amino acid addition salts are salts with glycine, phenylalanine,glutamic acid and lysine. Sulfonate salts include mesylate, tosylate andbenzene sulfonic acid salts.

In view of the close relationship between the compounds in free form andthose in the form of their salts, including those salts that can be usedas intermediates, for example in the purification or identification ofthe compounds, tautomers or tautomeric mixtures and their salts, anyreference to the compounds hereinbefore and hereinafter especially thecompounds of the formula I, is to be understood as referring also to thecorresponding tautomers of these compounds, especially of compounds ofthe formula I, tautomeric mixtures of these compounds, especially ofcompounds of the formula I, or salts of any of these, as appropriate andexpedient and if not mentioned otherwise.

Any asymmetric carbon atom may be present in the (R)-, (S)- or(R,S)-configuration, preferably in the (R)- or (S)-configuration.Substituents at a ring at atoms with saturated bonds may, if possible,be present in cis-(=Z-) or trans (=E-) form. The compounds may thus bepresent as mixtures of isomers or preferably as pure isomers, preferablyas enantiomer-pure diastereomers or pure enantiomers.

Preferred embodiments according to the invention:

In the following preferred embodiments, general expression can bereplaced by the corresponding more specific definitions provided aboveand below, thus yielding stronger preferred embodiments of theinvention.

Preferred is the USE of compounds of the formula I or pharmaceuticallyacceptable salts thereof, where the disease to be treated is aproliferative disease depending on binding of the Smac protein toinhibitor of Apoptosis Proteins (IAPS).

An embodiment of the present invention relates to compounds of theformula (I)

whereinR₁ is H; C₁-C₄ alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl or cycloalkyl whichare unsubstituted or substituted by one or more substituents selectedfrom halogen, —OH, —SH, —OCH₃, —SCH₃, —CN, —SCN and nitro;R₂ is H; C₁-C₄alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl or cycloalkyl whichare unsubstituted or substituted by one or more substituents selectedfrom halogen, —OH, —SH, —OCH₃, —SCH₃, —CN, —SCN and nitro;R₃ is H; —CF₃; —C₂F₅; C₁-C₄ alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl; —CH₂-Zor R₂ and R₃ together with the nitrogen form a het;

Z is H; —OH; F; Cl; —CH₃; —CF₃; —CH₂Cl; —CH₂F or —CH₂OH;

R₄ is C₁-C₁₆ straight or branched alkyl; C₁-C₁₆ alkenyl; C₁-C₁₆ alkynyl;or —C₃-C₁₆ cycloalkyl; —(CH₂)₁₋₆-Z₁; —(CH₂)₀₋₆-phenyl; and—(CH₂)₀₋₆-het, wherein alkyl, cycloalkyl and phenyl are unsubstituted orsubstituted;Z₁ is —N(R₈)—C(O)—C₁-C₁₀alkyl; —N(R₈)—C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—N(R₈)—C(O)—(CH₂)₀₋₆-phenyl; —N(R₈)—C(O)—(CH₂)₁₋₆-het; —C(O)—N(R₉)(R₁₀);—C(O)—O—C₁-C₁₀alkyl; —C(O)—O—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—C(O)—O—(CH₂)₀₋₆-phenyl; —C(O)—O—(CH₂)₁₋₆-het; —O—C(O)—C₁-C₁₀alkyl;—O—C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —O—C(O)—(CH₂)₀₋₆-phenyl;—O—C(O)—(CH₂)₁₋₆-het, wherein alkyl, cycloalkyl and phenyl areunsubstituted or substituted;het is a 5-7 membered heterocyclic ring containing 1-4 heteroatomsselected from N, O and S, or an 8-12 membered fused ring systemincluding at least one 5-7 membered heterocyclic ring containing 1, 2 or3 heteroatoms selected from N, O, and S, which heterocyclic ring orfused ring system is unsubstituted or substituted on a carbon atom byhalogen, hydroxy, C₁-C₄alkyl, C₁-C₄ alkoxy, nitro, —O—C(O)—C₁-C₄alkyl or—C(O)—O—C₁-C₄-alkyl or on a nitrogen by C₁-C₄ alkyl, —O—C(O)—C₁-C₄alkylor —C(O)—O—C₁-C₄alkyl;

R₈ is H, —CH₃, —CF₃, —CH₂OH or —CH₂Cl;

R₉ and R₁₀ are each independently H; C₁-C₄alkyl; C₃-C₇cycloalkyl;—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —(CH₂)₀₋₆-phenyl; wherein alkyl, cycloalkyland phenyl are unsubstituted or substituted, or R₉ and R₁₀ together withthe nitrogen form het;R₅ is H; C₁-C₁₀-alkyl; C₃-C₇cycloalkyl; —(CH₂)₁₋₆—C₃-C₇cycloalkyl;—C₁-C₁₀alkyl-aryl; —(CH₂)₀₋₆—C₃-C₇cycloalkyl-(CH₂)₀₋₆-phenyl;—(CH₂)₀₋₄CH—((CH₂)₁₋₄-phenyl)₂; —(CH₂)₀₋₆—CH(phenyl)₂;—(CH₂)₀₋₆—C(O)phenyl-indanyl; aryl —C(O)—C₁-C₁₀alkyl;—C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —C(O)—(CH₂)₀₋₆-phenyl; —(CH₂)₀₋₆-het;—C(O)—(CH₂)₁₋₆-het; or R₅ is a residue of an amino acid, wherein alkyl,cycloalkyl, phenyl and aryl are unsubstituted or substituted;U is a as shown in structure II:

whereinn=0-5;

X is —CH or N;

Ra and Rb are independently an O, S, or N atom or C₀₋₈ alkyl wherein oneor more of the carbon atoms in the alkyl chain may be replaced by aheteroatom selected from O, S or N, and where the alkyl may beunsubstituted or substituted;Rd is selected from:

-   -   (a) —Re-Q-(Rf)_(p)(Rg)_(q); or    -   (b) Ar₁-D-Ar₂;        Rc is H or Rd and Rc together form cycloalkyl or het; where if        Rd and Rc form a cycloalkyl or heteroring, R₅ is attached to the        formed ring at a C or N atom;        p and q are independently 0 or 1;        Re is C₁₋₈ alkyl, or alkylidene, preferably methylidene, and Re        may be unsubstituted or substituted;

Q is N, O, S, S(O), or S(O)₂;

Ar₁ and Ar₂ are substituted or unsubstituted aryl or het;Rf and Rg are each independently H; —C₁-C₁₀ alkyl; C₁-C₁₀alkylaryl; —OH;—O—C₁-C₁₀alkyl; —(CH₂)₀₋₆—C₃-C₇cycloalkyl; —O—(CH₂)₀₋₆-aryl; phenyl;aryl; phenyl-phenyl; —(CH₂)₁₋₆-het; —O—(CH₂)₁₋₆-het; —OR₁₁; —C(O)—R₁₁;—C(O)—N(R₁₁)(R₁₂); —N(R₁₁)(R₁₂); —S—R₁₁; —S(O)—R₁₁; —S(O)₂—R₁₁;—S(O)₂—NR₁₁R₁₂; —NR₁₁—S(O)₂—R₁₂; S—C₁-C₁-alkyl; aryl-C₁-C₄alkyl;het-C₁-C₄alkyl wherein alkyl, cycloalkyl, het and aryl are unsubstitutedor substituted; —SO₂—C₁-C₂alkyl; —SO₂—C₁-C₂alkylphenyl; —O—C₁-C₄alkyl;or R_(g) and R_(f) form a ring selected from het or aryl;D is —CO—; —C(O)—C₁₋₇ alkylene or arylene; —CF₂—; —O—; —S(O)_(r) where ris 0-2; 1,3dioaxolane; or C₁₋₇ alkyl-OH; where alkyl, alkylene orarylene may be unsubstituted or substituted with one or more halogens,OH, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃; or D is —N(Rh) wherein Rh isH; C₁₋₇ alkyl (unsub or substituted); aryl; —O(C₁₋₇cycloalkyl) (unsub orsubstituted); C(O)—C₁-C₁₀alkyl; C(O)—C_(o)—C₁₀alkylaryl;C—O—C₁-C₁₀alkyl; C—O—C_(o)—C₁₀alkyl-aryl or SO₂—C₁-C₁₀-alkyl;SO₂—(C_(o)—C₁₀-alkylaryl);R₆, R₇, R′₆ and R′₇ are each independently H; —C₁-C₁₀ alkyl; —C₁-C₁₀alkoxy; aryl-C₁-C₁₀ alkoxy; —OH; —O—C₁-C₁₀alkyl;—(CH₂)₀₋₆—C₃-C₇cycloalkyl; —O—(CH₂)₀₋₆-aryl; phenyl; —(CH₂)₁₋₆-het;—O—(CH₂)₁₋₆-het; —OR₁₁; —C(O)—R₁₁; —C(O)—N(R₁₁)(R₁₂); —N(R₁₁)(R₁₂);—S—R₁₁; —S(O)—R₁₁; —S(O)₂—R₁₁; —S(O)₂—NR₁₁R₁₂; —NR₁₁—S(O)₂—R₁₂; whereinalkyl, cycloalkyl and aryl are unsubstituted or substituted; and R₆, R₇,R′₆ and R′₇ can be united to form a ring system;R₁₁ and R₁₂ are independently H; C₁-C₁₀ alkyl;—(CH₂)₀₋₆—C₃-C₇cycloalkyl; —(CH₂)₀₋₆—(CH)₀₋₁(aryl)₁₋₂;—C(O)—C₁-C₁₀alkyl; —C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—C(O)—O—(CH₂)₀₋₆-aryl; —C(O)—(CH₂)₀₋₆—O-fluorenyl;—C(O)—NH—(CH₂)₀₋₆-aryl; —C(O)—(CH₂)₀₋₆-aryl; —C(O)—(CH₂)₁₋₆-het;—C(S)—C₁-C₁₀alkyl; —C(S)—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—C(S)—O—(CH₂)₀₋₆-aryl; —C(S)—(CH₂)₀₋₆—O-fluorenyl;—C(S)—NH—(CH₂)₀₋₆-aryl; —C(S)—(CH₂)₀₋₆-aryl; —C(S)—(CH₂)₁₋₆-het; whereinalkyl, cycloalkyl and aryl are unsubstituted or substituted; or R₁₁ andR₁₂ are a substituent that facilitates transport of the molecule acrossa cell membrane; or R₁₁ and R₁₂ together with the nitrogen are het; arylof R₁₁ and R₁₂ can be phenyl, naphthyl, or indanyl which isunsubstituted or substituted;alkyl of R₁₁ and R₁₂ may be unsubstituted or substituted by one or moresubstituents selected from a C₁-C₁₀ alkene, halogen, OH, —O—C₁-C₆alkyl,—S—C₁-C₆alkyl and —CF₃; cycloalkyl of R₁₁ and R₁₂ may be unsubstitutedor substituted by one or more selected from a C₁-C₁₀ alkene, one or morehalogens, C₁-C₆alkyl, halogen, OH, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃;andphenyl or aryl of R₁₁ and R₁₂ may be unsubstituted or substituted by oneor more substituents selected from halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄alkoxy, nitro, —CN, —O—C(O)—C₁-C₄alkyl and —C(O)—O—C₁-C₄-aryl;or pharmaceutically acceptable salts thereof.

A further embodiment the present invention relates to the use ofcompound of formula I in the treatment of proliferative diseases,especially those dependent on the binding of the Smac protein toInhibitor of Apoptosis Proteins (IAPs), or for the manufacture ofpharmaceutical compositions for use in the treatment of said diseases,methods of use of compounds of formula (I) in the treatment of saiddiseases, pharmaceutical preparations comprising compounds of formula(I) for the treatment of said diseases, compounds of formula (I) for usein the treatment of said diseases.

One embodiment of the present invention relates to compounds of theformula (I) wherein

R₁ and R₂ are independently H or substituted or unsubstitutedC₁-C₄alkyl;R₄ is C₁-C₁₆ straight or branched alkyl, or C₃-C₁₀cycloalkyl, whereinthe alkyl or cycloalkyl may be unsubstituted or substituted;R₅ is H; C₁-C₁₀alkyl; C₁-C₁₀alkyl-aryl; —C(O)—(CH₂)₀₋₆-Phenyl;—(CH₂)₀₋₆—C(O)-Phenyl; aryl; indanyl; naphthyl or R₅ is a residue of anamino acid, wherein the alkyl or aryl substituents are unsubstituted orsubstituted;U is as shown in structure II:

whereinn=0-5;

X is —CH or N;

Ra and Rb are independently an O, S, or N atom or C₀₋₈ alkyl wherein oneor more of the carbon atoms in the alkyl chain may be replaced by aheteroatom selected from O, S or N, and where the alkyl may beunsubstituted or substituted;Rd is selected from

-   -   (a) —Re-Q-(Rf)_(p)(Rg)_(q); or    -   (b) Ar₁-D-Ar₂;        Rc is H or Rc and Rd together form cycloalkyl or het; where if        Rd and Rc form a cycloalkyl or heteroring, R₅ is attached to the        formed ring at a C or N atom;        p and q are independently 0 or 1;        Re is C₁₋₈ alkyl, or methylidene which may be unsubstituted or        substituted;

Q is N, O, S, S(O), or S(O)₂;

Ar₁ and Ar₂ are substituted or unsubstituted aryl or het;Rf and Rg are each independently H or substituted or unsubstitutedC₀-C₁₀alkyl; C₁-C₁₀alkylaryl; aryl-C₁-C₁₀alkyl; het-C₁-C₁₀alkyl—C(O)—C₁-C₄-alkyl-phenyl; —C(O)—C₁-C₄-alkyl; —SO₂—C₁-C₂alkyl;—SO₂—C₁-C₂alkylphenyl; —O—C₁-C₄-alkyl;D is —C(O)—; C₁₋₇ alkylene or arylene; —O—, or —S(O)_(r) where r is 0-2;where alkyl, alkylene or arylene which may be unsubstituted orsubstituted with one or more halogens; —OH; —O—C₁-C₆alkyl; —S—C₁-C₆alkylor —CF₃; or D is NRh wherein Rh is H; C₁₋₇ alkyl (unsubstituted orsubstituted); aryl; —OC₁₋₇ cycloalkyl (unsubstituted or substituted);—CO—C₀₋₁₀ alkyl or aryl or SO₂—C₀₋₁₀-alkyl or aryl; and R₆, R₇, R′₆ andR′₇ are each independently H, —C₁-C₁₀ alkyl, or —OH, alkoxy, or aryloxy;or pharmaceutically acceptable salts thereof.

In a further embodiment, U is a bicyclic saturated or unsaturated ringsystem, consisting of all carbon skeleton or with one or moreheteroatoms such as O, N, S but preferably as shown in structure III:

whereinwherein any of the ring carbon atoms can be unsubstituted or substitutedwith any of the substituted defined above for R₆, R₇, R_(6′) and R₇′;

X is CH or N;

V is O, F₂, Cl₂, Br₂, I₂, S, YH, H₂, NH, or C₁-C₄ alkyl;

W is —CH, or —N;

n is 0-3; andm is 0-3.

In a preferred embodiment the ring atoms may be substituted withsubstituents independently selected from halo, H, OH, lower alkyl orlower alkoxy, wherein alkyl or alkoxy are unsubstituted or substitutedby halogen, OH, lower alkyl or lower alkoxy.

In a further embodiment, U of formula II or III together with R₅ form afused ring system.

Especially preferred is a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H; methyl; ethyl; chloromethyl; dichloromethyl ortrifluoromethyl;R₄ is —C₁-C₄alkyl; —C₃-C₇ cycloalkyl; —(CH₂)₁₋₆cycloalkyl; or—(CH₂)₀₋₆aryl. R₄ is particularly ethyl; propyl; isopropyl; t-butyl;cyclopentyl; or cyclohexyl; —CH₂-cyclopentyl; —CH₂-cyclohexyl or—CH₂-phenyl.R₅ is —C₁-C₄alkyl-phenyl; —C(O)—C₁-C₄alkyl-phenyl;—C₁-C₄alkyl-C(O)-pheny or aryl; R₅ is particularly phenylmethyl,phenylethyl and phenylpropyl; indanyl, naphthyl; —C(O)—CH₂-phenyl or—CH₂—C(O)-phenyl;R₆ and R₇ are H or methyl;U has the structure of formula III:

whereinwherein any of the ring carbon atoms can be unsubstituted or substitutedwith any of the substituted defined above for R₆, R₇, R_(6′) and R₇′;

X is N; V is O or H₂; W is —N;

n is 1; andm is 1 or 2.

Especially preferred is a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;

R₂ is H;

R₄ is C₁-C₄alkyl; C₃-C₇ cycloalkyl; C₁-C₇ cycloalkyl-C₁-C₇alkyl;phenyl-C₁-C₇alkyl or aryl. R₄ is particularly methyl; ethyl; butyl;isopropyl; t-butyl; or cyclohexyl; —CH₂-cyclopentyl; —CH₂-cyclohexyl;—CH₂-cyclopropyl; phenyl or —CH₂-phenyl;R₅ is —C₁-C₄alkyl-phenyl; —C(O)—C₁-C₄alkyl-phenyl;—C₁-C₄alkyl-C(O)-pheny or aryl. R₅ is particularly phenylethyl; indanyl,naphthyl; —C(O)—CH₂-phenyl; —CH₂—C(O)-phenyl or (CF₃O)phenylethyl;

R₆, R′₆, R₇ and R′₇ are H;

U has the structure of formula III whereinwherein any of the ring carbon atoms can be unsubstituted or substitutedwith any of the substituted defined above for R₆, R₇, R_(6′) and R₇′;

X is N; V is O or H₂; W is —N;

n is 1; andm is 1 or 2.

Another embodiment is directed to a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl;R₄ is C₁-C₄alkyl or C₃-C₇ cycloalkyl particularly isopropyl, t-butyl,cyclopentyl, or cyclohexyl;

R₅ is H;

U has the structure of formula II wherein

X is N; R₆, R′₆, R₇, and R′₇ are H; n is O; Rc is H;

Ar₁ and Ar₂ are substituted or unsubstituted phenyl or het particularlytetrazolyl, 1, 2,3-triazole, pyrazole, oxazole, pyrrolyl, triazine,pyrimidine, imidazol, oxadiazol; and and D is C₁ alkyl which mayoptionally be substituted with halo, especially F.

Another embodiment is directed to a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl;R₄ is C₁-C₄alkyl; C₃-C₇ cycloalkyl; C₁-C₇ cycloalkyl-C₁-C₇alkyl;phenyl-C₁-C₇alkyl or aryl. R₄ is particularly methyl, ethyl, butyl,isopropyl, t-butyl, or cyclohexyl; —CH₂-cyclopentyl, —CH₂-cyclohexyl;—CH₂-cyclopropyl; phenyl or —CH₂-phenyl;

R₅ is H;

U has the structure of formula II wherein

X is N;

R₆, R′₆, R₇, and R′₇ are H; or R₆ is —C(O)—C₁-C₄alkyl-phenyl and R′₆,R₇, and R′₇ are H;

n is O; Rc is H;

Ar₁ and Ar₂ are substituted or unsubstituted phenyl or het, particularlytriazine, pyrimidine, pyridine, oxazole, 2,4-difluorophenyl, Cl-phenylor fluorophenyl; and D is N(Rh), where Rh is H, Me, —CHO, —SO₂, —C(O),—CHOH, —CF₃ or —SO₂CH₃.

Another embodiment is directed to a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl;R₄ is C₁-C₄alkyl; C₃-C₇cycloalkyl; C₁-C₇cycloalkyl-C₁-C₇alkyl;phenyl-C₁-C₇alkyl or aryl. R₄ is particularly methyl, ethyl, butyl,isopropyl, t-butyl, or cyclohexyl; —CH₂-cyclopentyl, —CH₂-cyclohexyl;—CH₂-cyclopropyl; phenyl or —CH₂-phenyl;

R₅ is H;

U has the structure of formula II wherein

X is N; R₆, R′₆, R₇, and R′₇ are H; n is O; Rc is H;

Ar₁ and Ar₂ are substituted or unsubstituted phenyl or het particularlypyrimidine, pyridine, oxazole, 2-methyloxazole; and D is —O—.

Another embodiment is directed to a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl;R₄ is C₁-C₄alkyl or C₃-C₇cycloalkyl particularly isopropyl, t-butyl,cyclopentyl, or cyclohexyl;

R₅ is H;

U has the structure of formula II wherein

X is N; R₆, R′₆, R₇, and R′₇ are H; n is O; Rc is H;

Ar₁ and Ar₂ are substituted or unsubstituted phenyl or het; and D is S,S(O), or S(O)₂.

Another embodiment is directed to a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl;R₄ is C₁-C₄alkyl or C₃-C₇cycloalkyl particularly isopropyl, t-butyl,cyclopentyl, or cyclohexyl;

R₅ is H;

U has the structure of formula II wherein

X is N; R₆, R′₆, R₇, and R′₇ are H; n is O; Rc is H;

Ar₁ and Ar₂ are substituted or unsubstituted phenyl or het, particularlyoxazole, thaizole and ozadiazole;and D is C(O), or 1,3-dioxolane.

Another embodiment is directed to a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl;R₄ is C₁-C₄alkyl or C₃-C₇cycloalkyl particularly isopropyl, t-butyl,cyclopentyl, or cyclohexyl;R₅ is H or phenyl C₁-C₁₀alkyl such as phenylethyl;U has the structure of formula II wherein

X is N; R₆, R′₆, R₇, and R′₇ are H; n is O;

Rc and Rd are a heterocyclic ring, particularly pyrrolidine;pyrrolidin-2-one; or pyrrolidin-3-one.

Another embodiment is directed to a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl;R₄ is C₁-C₄alkyl or C₃-C₇ cycloalkyl particularly isopropyl, t-butyl,cyclopentyl, or cyclohexyl;R₅ is H, indanyl or phenyl;U has the structure of formula II wherein

X is N; Q is O; R₆, R′₆, R₇, and R′₇ are H; n is O;

Re is C₁ alkyl; andp and q are 0.

A further embodiment is directed to a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl;R₄ is C₁-C₄alkyl or C₃-C₇ cycloalkyl particularly isopropyl, t-butyl,cyclopentyl, or cyclohexyl;R₅ is H, indanyl or phenyl;U has the structure of formula II wherein

X is N; Q is N; R₆, R′₆, R₇, and R′₇ are H; n is O;

Re is C₁ alkyl; andR_(g) is H C₁-C₈ alkyl, methyl, ethyl, hexyl, heptyl, octyl; or CH₂CF₃;or aryl-C₁-C₄ alkyl particularly phenylethyl, furanylethyl;C₃-C₇cycloalkyl particularly cyclohexyl; ethylphenyl;—C(O)—C₁-C₄alkyl-phenyl; —C(O)—C₁-C₄alkyl; —C₁-C₄alkyl-aryl particularly—CH₂-phenyl; —CH₂-thiophene, —CH₂-furan, —CH₂-pyrrolidinyl,—CH₂-imidazole, —CH₂-triazole, —CH₂-imidazole;and R_(f) is C₁-C₂ alkyl; C₁-C₂alkylphenyl; —SO₂—C₁-C₂alkyl;—SO₂—C₁-C₂alkylphenyl; —O—C₁-C₄alkyl particularly O-ethyl;phenyl-phenyl, 1,2,3,4-tetrahydronapthalene and indanyl.

A further embodiment is directed to a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl;R₄ is C₁-C₄alkyl or C₃-C₇ cycloalkyl particularly isopropyl, t-butyl,cyclopentyl, or cyclohexyl;R₅ is H, indanyl or phenyl;U has the structure of formula II wherein

X is N; Q is N; R₆, R′₆, R₇, and R′₇ are H; n is O;

Re is C₁ alkyl; andR_(g) and R_(f) form a ring selected from het or aryl particularly2,3,4,5-tetrahydrobenzo[c]azepine; 1,2,3,4 tetrahydroquinoline; indanylwhich may be substituted with C₁-C₄alkylphenyl

A further embodiment is directed to a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl;R₄ is C₁-C₄alkyl or C₃-C₇ cycloalkyl particularly isopropyl, t-butyl,cyclopentyl, or cyclohexyl;R₅ is phenyl;U has the structure of formula II wherein

X is N; Q is O, S, S(O) or S(O)₂; R₆, R′₆, R₇, and R′₇ are H; n is O;

Re is C₁ alkyl;q is 0;

Rc is H;

and R_(f) is C₂ alkyl.

A further embodiment is directed to a compound of formula (I) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl;R₄ is C₁-C₄alkyl or C₃-C₇ cycloalkyl particularly isopropyl, t-butyl,cyclopentyl, or cyclohexyl;R₅ is phenyl;U has the structure of formula II wherein

X is N; Q is N; R₆, R′₆, R₇, and R′₇ are H; n is O; Re is CH;

q is 0;

Rc is H;

and R_(f) is OC₁ alkyl.

In a particularly important embodiment of the present invention, R₃ andR₄ have the stereochemistry indicated in formula IV, with thedefinitions of the variable substituents and preferences describedherein above also applying to compounds having the stereochemistryindicated in formula IV.

Especially preferred is a compound with the stereochemistry of formula(IV) wherein

R₁ and R₃ are preferably methyl or ethyl;R₂ is H, methyl, ethyl, or substituted methyl especially chloromethyl,dichloromethyl and trifluoromethyl; preferably R₂ is H or unsubstitutedmethyl;R₄ is C₁-C₄alkyl or C₃-C₇ cycloalkyl particularly isopropyl, t-butyl,cyclopentyl, or cyclohexyl;R₅ is —C₁-C₄-alkyl-phenyl, particularly phenylmethyl, phenylethyl andphenylpropyl, indanyl, naphthyl; andR₆ and R₇ are H or methyl.

The preferred stereochemistry for U is as shown in Figure V

In a particular embodiment of the present invention, one or both of R₆,R₇, R_(6′), and R_(7′) is H. If one of R₆, R₇, R_(6′), and R_(7′) isother than H, it is especially hydroxyl or phenoxy.

Synthetic Procedure ABBREVIATIONS

-   CH₂Cl₂ methylene chloride-   CH₃CN acetonitrile-   DIBAL diisobutylaluminium hydride-   DIPEA diisopropylethylamine-   DME ethylene glycol dimethyl ether-   DMF N,N-dimethylformamide-   DTBB 4,4′-di-tert-butylbiphenyl-   EtOAc ethyl acetate-   HBTU O-benzyltriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBt 1-hydroxhbenzotriazole-   HPLC high pressure liquid chromatography-   KOTMS potassium trimethysilanoate.-   MeOH methanol-   MgSO₄ magnesium sulfate-   MnO₂ manganese dioxide-   Na₂CO₃ sodium carbonate-   NaHCO₃ sodium bicarbonate-   NaOH sodium hydroxide-   Tetrakis tetrakis(triphenylphosphine)palladium(0)-   TFA trifluoroacetic acid-   THF tetrahydrofuran

The compounds of formula (I) may be prepared as depicted below in scheme1 (for compound #9-25, 29-31):

General synthesis scheme for compounds of formula I where W═N and X andX′ are independently selected from the subsituents defined above for R₆:

KOTMS is defined as potassium trimethysilanoate.

Step A: This step involves the formation of an aziridine ring viastandard base mediated conditions.

Step B: This step involves the formation of a secondary amine via thereaction of an alkyl bromide with excess amine in the presence of abase.

Step C: This step involves the coupling of a secondary amine with anactivated derivative of the aziridine methyl ester to form an amidesubstituted aziridine.

Step D: This step involves the intramolecular cycloaddition of theaziridine to the tethered alkene through a thermally accessibleazomethine ylide intermediate.

Step E: This step involves the reduction of the amide to an amine viastandard reduction conditions employing DIBAL-H.

Step F: This step involves the removal of the benzylic protecting groupusing standard palladium conditions under a hydrogen atmosphere.

Step G: This step involves coupling of the scaffold with a t-Bocprotected natural or unnatural amino acid using standard peptidecoupling conditions followed by the removal of the t-Boc group with TFA.

Step H: This step involves the coupling of the amine generated in thepreceding step with a t-Boc protected or tertiary natural or unnaturalamino acid using standard peptide coupling conditions followed by theremoval of the t-Boc group with TFA if applicable. The product is thenpurified by high-performance liquid chromatography (HPLC).

The compounds of formula (I) may be prepared as depicted below in scheme2 (for compound #26-28):

The compounds of formula (I) may be prepared as depicted below in scheme3 (for compound #32-33):

The compounds of formula (I) may be prepared as depicted below in scheme4 (for compound #34-35):

Compounds 36-38 can be prepared analogously to the preparation ofcompounds 34-35 according to Scheme 4.

As discussed above, the compounds of the present invention are usefulfor treating proliferative diseases. Thus, the present invention furtherrelates to a method of treating a proliferative disease which comprisesadministering a therapeutically effective amount of a compound of theinvention to a mammal, preferably a human, in need of such treatment.

A proliferative disease is mainly a tumor disease (or cancer) (and/orany metastases). The inventive compounds are particularly useful fortreating a tumor which is a breast cancer, genitourinary cancer, lungcancer, gastrointestinal cancer, epidermoid cancer, melanoma, ovariancancer, pancreas cancer, neuroblastoma, head and/or neck cancer orbladder cancer, or in a broader sense renal, brain or gastric cancer; inparticular (i) a breast tumor; an epidermoid tumor, such as anepidermoid head and/or neck tumor or a mouth tumor; a lung tumor, forexample a small cell or non-small cell lung tumor; a gastrointestinaltumor, for example, a colorectal tumor; or a genitourinary tumor, forexample, a prostate tumor (especially a hormone-refractory prostatetumor); or (ii) a proliferative disease that is refractory to thetreatment with other chemotherapeutics; or (iii) a tumor that isrefractory to treatment with other chemotherapeutics due to multidrugresistance.

In a broader sense of the invention, a proliferative disease mayfurthermore be a hyperproliferative condition such as leukemias,hyperplasias, fibrosis (especially pulmonary, but also other types offibrosis, such as renal fibrosis), angiogenesis, psoriasis,atherosclerosis and smooth muscle proliferation in the blood vessels,such as stenosis or restenosis following angioplasty.

Where a tumor, a tumor disease, a carcinoma or a cancer are mentioned,also metastasis in the original organ or tissue and/or in any otherlocation are implied alternatively or in addition, whatever the locationof the tumor and/or metastasis.

The inventive compound is selectively toxic or more toxic to rapidlyproliferating cells than to normal cells, particularly in human cancercells, e.g., cancerous tumors, the compound has significantantiproliferative effects and promotes differentiation, e.g., cell cyclearrest and apoptosis.

The compounds of the present invention may be administered alone or incombination with other anticancer agents, such as compounds that inhibittumor angiogenesis, for example, the protease inhibitors, epidermalgrowth factor receptor kinase inhibitors, vascular endothelial growthfactor receptor kinase inhibitors and the like; cytotoxic drugs, such asantimetabolites, like purine and pyrimidine analog antimetabolites;antimitotic agents like microtubule stabilizing drugs and antimitoticalkaloids; platinum coordination complexes; anti-tumor antibiotics;alkylating agents, such as nitrogen mustards and nitrosoureas; endocrineagents, such as adrenocorticosteroids, androgens, anti-androgens,estrogens, anti-estrogens, aromatase inhibitors, gonadotropin-releasinghormone agonists and somatostatin analogues and compounds that target anenzyme or receptor that is overexpressed and/or otherwise involved aspecific metabolic pathway that is upregulated in the tumor cell, forexample ATP and GTP phosphodiesterase inhibitors, histone deacetylaseinhibitors, protein kinase inhibitors, such as serine, threonine andtyrosine kinase inhibitors, for example, Abelson protein tryosine kinaseand the various growth factors, their receptors and kinase inhibitorstherefore, such as, epidermal growth factor receptor kinase inhibitors,vascular endothelial growth factor receptor kinase inhibitors,fibroblast growth factor inhibitors, insulin-like growth factor receptorinhibitors and platelet-derived growth factor receptor kinase inhibitorsand the like; methionine aminopeptidase inhibitors, proteasomeinhibitors, and cyclooxygenase inhibitors, for example, cyclooxygenase-1or -2 inhibitors.

The present invention further relates to a method of promoting apoptosisin rapidly proliferating cells, which comprises contacting the rapidlyproliferating cells with an effective apoptosis promoting amount of anon-naturally-occurring compound that binds to the Smac binding site ofXIAP and/or cIAP proteins. Preferably, the non-naturally-occurringcompound a compound of present formula I or IV.

The present invention further relates to a method of treating orinhibiting myeloma, especially multiple myeloma. The term “myeloma” asused herein relates to a tumor composed of cells of the type normallyfound in the bone marrow. The term “multiple myeloma” as used hereinmeans a disseminated malignant neoplasm of plasma cells which ischaracterized by multiple bone marrow tumor foci and secretion of an Mcomponent (a monoclonal immunoglobulin fragment), associated withwidespread osteolytic lesions resulting in bone pain, pathologicfractures, hypercalcaemia and normochromic normocytic anaemia. Multiplemyeloma is incurable by the use of conventional and high dosechemotherapies. The invention relates to a method of treating myeloma,especially myeloma which is resistant to conventional chemotherapy.

Pharmaceutical Compositions

The invention relates also to pharmaceutical compositions comprising acompound of formula I, to their use in the therapeutic (in a broaderaspect of the invention also prophylactic) treatment or a method oftreatment of a kinase dependent disease, especially the preferreddiseases mentioned above, to the compounds for said use and topharmaceutical preparations and their manufacture, especially for saiduses.

The present invention also relates to pro-drugs of a compound of formulaI that convert in vivo to the compound of formula I as such. Anyreference to a compound of formula I is therefore to be understood asreferring also to the corresponding pro-drugs of the compound of formulaI, as appropriate and expedient.

The pharmacologically acceptable compounds of the present invention maybe present in or employed, for example, for the preparation ofpharmaceutical compositions that comprise an effective amount of acompound of the formula I, or a pharmaceutically acceptable saltthereof, as active ingredient together or in admixture with one or moreinorganic or organic, solid or liquid, pharmaceutically acceptablecarriers (carrier materials).

The invention relates also to a pharmaceutical composition that issuitable for administration to a warm-blooded animal, especially a human(or to cells or cell lines derived from a warm-blooded animal,especially a human, e.g. lymphocytes), for the treatment of (this, in abroader aspect of the invention, also includes the prevention of(=prophylaxis against)) a disease that responds to inhibition of proteinkinase activity, comprising an amount of a compound of formula I or apharmaceutically acceptable salt thereof, preferably which is effectivefor said inhibition, together with at least one pharmaceuticallyacceptable carrier.

The pharmaceutical compositions according to the invention are those forenteral, such as nasal, rectal or oral, or parenteral, such asintramuscular or intravenous, administration to warm-blooded animals(especially a human), that comprise an effective dose of thepharmacologically active ingredient, alone or together with asignificant amount of a pharmaceutically acceptable carrier. The dose ofthe active ingredient depends on the species of warm-blooded animal, thebody weight, the age and the individual condition, individualpharmacokinetic data, the disease to be treated and the mode ofadministration.

The invention relates also to a method of treatment for a disease thatresponds to inhibition of a protein kinase and/or a proliferativedisease, which comprises administering a (against the mentioneddiseases) prophylactically or especially therapeutically effectiveamount of a compound of formula I according to the invention, or atautomer thereof or a pharmaceutically acceptable salt thereof,especially to a warm-blooded animal, for example a human, that, onaccount of one of the mentioned diseases, requires such treatment.

The dose of a compound of the formula I or a pharmaceutically acceptablesalt thereof to be administered to warm-blooded animals, for examplehumans of approximately 70 kg body weight, preferably is fromapproximately 3 mg to approximately 10 g, more preferably fromapproximately 10 mg to approximately 1.5 g, most preferably from about100 mg to about 1000 mg/person/day, divided preferably into 1-3 singledoses which may, for example, be of the same size. Usually, childrenreceive half of the adult dose.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, dragées, tablets or capsules.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional dissolving,lyophilizing, mixing, granulating or confectioning processes.

Combinations

A compound of the formula I may also be used to advantage in combinationwith other antiproliferative agents. Such antiproliferative agentsinclude, but are not limited to aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive agents; alkylating agents; histone deacetylase inhibitors;compounds which induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity and further anti-angiogenic compounds;compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase; gonadorelin agonists; anti-androgens; methionineaminopeptidase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; agents used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors; temozolomide (TEMODAL®); and leucovorin.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane can be administered,e.g., in the form as it is marketed, e.g. under the trademark AROMASIN.Formestane can be administered, e.g., in the form as it is marketed,e.g. under the trademark LENTARON. Fadrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark AFEMA.Anastrozole can be administered, e.g., in the form as it is marketed,e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, e.g. breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g. under the trademark NOLVADEX.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA. Fulvestrant can be formulatedas disclosed in U.S. Pat. No. 4,659,516 or it can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FASLODEX. Acombination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, e.g. breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (CASODEX), which canbe formulated, e.g. as disclosed in U.S. Pat. No. 4,636,505.

The term “gonadorelin agonist” as used herein includes, but is notlimited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX. Abarelixcan be formulated, e.g. as disclosed in U.S. Pat. No. 5,843,901.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148 (compound A1 in WO99/17804). Irinotecan can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark CAMPTOSAR. Topotecan can be administered, e.g., in the form asit is marketed, e.g. under the trademark HYCAMTIN.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, e.g. CAELYX), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide can be administered, e.g. in the form as it is marketed, e.g.under the trademark ETOPOPHOS. Teniposide can be administered, e.g. inthe form as it is marketed, e.g. under the trademark VM 26-BRISTOL.Doxorubicin can be administered, e.g. in the form as it is marketed,e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark FARMORUBICIN. Idarubicin can be administered, e.g. in the formas it is marketed, e.g. under the trademark ZAVEDOS. Mitoxantrone can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark NOVANTRON.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing agents and microtublin polymerizationinhibitors including, but not limited to taxanes, e.g. paclitaxel anddocetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastinesulfate, vincristine especially vincristine sulfate, and vinorelbine,discodermolides, cochicine and epothilones and derivatives thereof, e.g.epothilone B or D or derivatives thereof. Paclitaxel may be administerede.g. in the form as it is marketed, e.g. TAXOL. Docetaxel can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark TAXOTERE. Vinblastine sulfate can be administered, e.g., inthe form as it is marketed, e.g. under the trademark VINBLASTIN R.P.Vincristine sulfate can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FARMISTIN. Discodermolide can beobtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also includedare Epothilone derivatives which are disclosed in WO 98/10121, U.S. Pat.No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO00/31247. Especially preferred are Epothilone A and/or B.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide can be administered, e.g., in the form as itis marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HOLOXAN.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes compounds disclosed in WO02/22577, especiallyN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideand pharmaceutically acceptable salts thereof. It further especiallyincludes Suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingagents, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabinecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark XELODA. Gemcitabine can be administered, e.g., in the form asit is marketed, e.g. under the trademark GEMZAR. Also included is themonoclonal antibody trastuzumab which can be administered, e.g., in theform as it is marketed, e.g. under the trademark HERCEPTIN.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity and further anti-angiogenic compounds” as used herein includes,but is not limited to: protein tyrosine kinase and/or serine and/orthreonine kinase inhibitors or lipid kinase inhibitors, e.g.:

a) compounds targeting, decreasing or inhibiting the activity of thefibroblast growth factor-receptors (FGF-Rs);b) compounds targeting, decreasing or inhibiting the activity of theinsulin-like growth factor receptor I (IGF-IR), such as compounds whichtarget, decrease or inhibit the activity of IGF-IR, especially compoundswhich inhibit the IGF-IR receptor, such as those compounds disclosed inWO 02/092599;c) compounds targeting, decreasing or inhibiting the activity of the Trkreceptor tyrosine kinase family;d) compounds targeting, decreasing or inhibiting the activity of the Axlreceptor tyrosine kinase family;e) compounds targeting, decreasing or inhibiting the activity of thec-Met receptor;f) compounds targeting, decreasing or inhibiting the activity of membersof the protein kinase C (PKC) and Raf family of serine/threoninekinases, members of the MEK, SRC, JAK, FAK, PDK and Ras/MAPK familymembers, or PI(3) kinase family, or of the PI(3)-kinase-related kinasefamily, and/or members of the cyclin-dependent kinase family (CDK) andare especially those staurosporine derivatives disclosed in U.S. Pat.No. 5,093,330, e.g. midostaurin; examples of further compounds includee.g. UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds such as those disclosed in WO00/09495; FTIs; PD184352 or QAN697 (a P13K inhibitor);g) compounds targeting, decreasing or inhibiting the activity of aprotein-tyrosine kinase, such as imatinib mesylate (GLIVEC/GLEEVEC) ortyrphostin. A tyrphostin is preferably a low molecular weight (Mr<1500)compound, or a pharmaceutically acceptable salt thereof, especially acompound selected from the benzylidenemalonitrile class or theS-arylbenzenemalonirile or bisubstrate quinoline class of compounds,more especially any compound selected from the group consisting ofTyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748;Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer;Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); andh) compounds targeting, decreasing or inhibiting the activity of theepidermal growth factor family of receptor tyrosine kinases (EGF-R,ErbB2, ErbB3, ErbB4 as homo- or heterodimers), such as compounds whichtarget, decrease or inhibit the activity of the epidermal growth factorreceptor family are especially compounds, proteins or antibodies whichinhibit members of the EGF receptor tyrosine kinase family, e.g. EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,and are in particular those compounds, proteins or monoclonal antibodiesgenerically and specifically disclosed in WO 97/02266, e.g. the compoundof ex. 39, or in EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP0 787 722, EP 0 837 063, U.S. Pat. No. 5,747,498, WO 98/10767, WO97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/30347 (e.g.compound known as CP 358774), WO 96/33980 (e.g. compound ZD 1839) and WO95/03283 (e.g. compound ZM105180); e.g. trastuzumab (HERCEPTIN),cetuximab, Iressa, Tarceva, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5,E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidinederivatives which are disclosed in WO 03/013541.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (THALOMID) and TNP-470.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,PTEN or CDC25, e.g. okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes are e.g. retinoicacid, α- γ- or δ-tocopherol or α- γ- or δ-tocotrienol.

The term “cyclooxygenase inhibitor” as used herein includes, but is notlimited to, e.g. Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, e.g.5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779and ABT578.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. “Etridonic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark DIDRONEL. “Clodronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark BONEFOS. “Tiludronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark SKELID. “Pamidronic acid” can be administered, e.g.in the form as it is marketed, e.g. under the trademark AREDIA™.“Alendronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FOSAMAX. “Ibandronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONDRANAT. “Risedronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ACTONEL. “Zoledronicacid” can be administered, e.g. in the form as it is marketed, e.g.under the trademark ZOMETA.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulphate degradation. The termincludes, but is not limited to, PI-88.

The term “biological response modifier” as used herein refers to alymphokine or interferons, e.g. interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g. H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras e.g. a “farnesyl transferaseinhibitor”, e.g. L-744832, DK8G557 or R115777 (Zarnestra).

The term “telomerase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of telomerase. Compounds whichtarget, decrease or inhibit the activity of telomerase are especiallycompounds which inhibit the telomerase receptor, e.g. telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase are e.g. bengamide or a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasome includee.g. PS-341 and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP inhibitor”) asused herein includes, but is not limited to collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “agents used in the treatment of hematologic malignancies” asused herein includes, but is not limited to FMS-like tyrosine kinaseinhibitors e.g. compounds targeting, decreasing or inhibiting theactivity of Flt-3; interferon, 1-b-D-arabinofuransylcytosine (ara-c) andbisulfan; and ALK inhibitors e.g. compounds which target, decrease orinhibit anaplastic lymphoma kinase.

The term “compounds which target, decrease or inhibit the activity ofFlt-3” are especially compounds, proteins or antibodies which inhibitFlt-3, e.g. PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteasome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90 e.g., 17-allylamino, 17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to trastuzumab (Herceptin™), Trastuzumab-DM1, erlotinib(Tarceva™), bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553(anti-CD40) and 2C4 Antibody. By antibodies is meant e.g. intactmonoclonal antibodies, polyclonal antibodies, multispecific antibodiesformed from at least 2 intact antibodies, and antibodies fragments solong as they exhibit the desired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of formulaI can be used in combination with standard leukemia therapies,especially in combination with therapies used for the treatment of AML.In particular, compounds of formula I can be administered in combinationwith e.g. farnesyl transferase inhibitors and/or other drugs useful forthe treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16,Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

The above-mentioned compounds, which can be used in combination with acompound of the formula I, can be prepared and administered as describedin the art such as in the documents cited above.

A compound of the formula I may also be used to advantage in combinationwith known therapeutic processes, e.g., the administration of hormonesor especially radiation.

A compound of formula I may in particular be used as a radiosensitizer,especially for the treatment of tumors which exhibit poor sensitivity toradiotherapy.

By “combination”, there is meant either a fixed combination in onedosage unit form, or a kit of parts for the combined administrationwhere a compound of the formula I and a combination partner may beadministered independently at the same time or separately within timeintervals that especially allow that the combination partners show acooperative, e.g. synergistic, effect, or any combination thereof.

EXAMPLES

The following examples are intended to illustrate, but not furtherlimit, the invention.

Example 1N-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide(9);

Compound 9 according to Formula I is prepared according to the procedureset forth in Scheme 5.

1-(1-Naphthalen-1-yl-ethyl)-aziridine-2-carboxylic acid methyl ester(1). To a solution of (S)-(−)-1-(1-naphthyl)ethylamine (20.8 g, 120mmol) in acetonitrile (HPLC grade, 600 mL) is added K₂CO₃ (52.7 g, 360mmol) and methyl 2,3-dibromopropionate (30 g, 120 mmol). The solution isstirred overnight at room temperature. The solution is evaporated todryness, then H₂O/EtOAc (1:1) (600 mL) is added, and the mixture isextracted with EtOAc (4×100 mL). The organic extracts are combined,dried and concentrated under vacuum. The residue is purified by flashchromatography (silica gel; Hexane/EtOAc 1:2) to provide 24 g (78%) ofthe title compound as a mixture of two diastereomers in an equimolecularratio. M+H⁺=256.10.

But-3-enyl-phenethyl-amine (2). To a solution of 2-phenylethylamine (72mL, 570 mmol) is added K₂CO₃ (82 g, 570 mmol) and 4-bromo-1-butene (25g, 185 mmol). The solution is stirred overnight at room temperature. Thesolution is evaporated to dryness and H₂O/EtOAc (1:1) (600 mL) is added.The mixture is extracted with EtOAc (4×150 mL). The organic extracts arecombined, dried and concentrated under vacuum. The residue is purifiedby flash chromatography (silica gel; Hexane/EtOAc 1:8) to provide 20 g(62%) of the title compound. M+H⁺=176.10.

1-(1-Naphthalen-1-yl-ethyl)-aziridine-2-carboxylic acidbut-3-enyl-phenethyl-amide (3). To a solution of 1 (12.6 g, 49.75 mmol)in THF (200 mL) is added KOTMS (6.38 g, 49.75 mmol). The mixture isstirred overnight at room temperature. The mixture is concentrated andthe residue dissolved in dichloromethane (200 mL) and cooled to 0° C.Trimethylacetyl chloride (5.94 g, 49.25 mmol) is added slowly and themixture is warmed to room temperature over 2 hours. The mixture iscooled to −78° C., 2 (8.63 g, 49.25 mmol) is added and stirringcontinued at −78° C. for 1.5 h. Saturated sodium bicarbonate (100 mL) isadded and the mixture is allowed to warm to rt. The mixture is extractedwith EtOAc (4×100 mL) and the organic extracts are combined, dried andconcentrated under vacuum. The residue is purified by flashchromatography (silica gel; Hexane/EtOAc 1:8) to provide 15 g (76%) ofthe title compound as a mixture of two diastereomers in an equimolecularratio. M+H⁺=399.37.

1-(1-Naphthalen-1-yl-ethyl)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-7-one(4). A solution of 3 (15 g, 58.7 mmol) in o-dichlorobenzene (100 mL) isheated at 250° C. for 1200 s in a microwave reactor. The mixture ispurified by flash chromatography (silica gel; Hexane/EtOAc 1:1; secondspot) to provide 5 g (33%) of the title compound as an enantiomericallypure compound. M+H⁺=399.32.

1-(1-Naphthalen-1-yl-ethyl)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine(5). To a solution of 4 (4.8 g, 12 mmol) in THF (100 mL) is added slowly1 M DIBAL in toluene, (50 mL, 50 mmol) at −78° C. The mixture is stirredat room temperature for 1 hour and quenched with 20 mL of water. Thesolvent is evaporated, the residue is diluted with 100 mL of 1:1saturated Rochells salt/15% NaOH, and this extracted with EtOAc (4×50mL). The organic extracts are combined, dried and concentrated undervacuum. The residue is purified by flash chromatography (silica gel;Hexane/EtOAc 1:9) to provide 2.3 g (48%) of the title compound.M+H⁺=385.26.

6-Phenethyl-octahydro-pyrrolo[2,3-c]pyridine (6). To a solution of 5(2.3 g, 6 mmol) in MeOH/CH₂Cl₂ (1:1; 200 mL) is added Pd(OH)₂ (300 mg).The mixture is agitated under 50 psi. hydrogen atmosphere for 10 h. Themixture is filtered through a celite pad, the filtrate is concentratedand the residue is used directly in the next step without furtherpurification. M+H⁺=231.17.

Compound (7). To a solution of 6 in dichloromethane (25 mL) is addedsequentially diisopropylethylamine (4.17 mL, 24 mmol),t-Boc-L-cyclohexylglycine (1.54 g, 6 mmol), and a solution of 0.45 MHOBt/HBTU in DMF (16 mL, 7.19 mmol). The mixture is stirred overnight atroom temperature, then diluted with EtOAc (200 mL) and washedsequentially with 1 M aq. citric acid (50 mL), water (50 mL), aq. Sat.NaHCO₃ (50 mL) and brine (2×50 mL). The organic layer is dried andconcentrated under vacuum. The residue is purified by flashchromatography (silica gel; Hexane/EtOAc 1:9) to provide a yellow oil.The yellow oil is dissolved in dichloromethane (20 mL), TFA (10 mL) isadded and the mixture is stirred at room temperature for 3 h. Themixture is concentrated and the residue is dissolved in dichloromethane(100 mL) and neutralized with saturated sodium bicarbonate. The solutionis extracted with dichloromethane (3×50 mL). The organic extracts arecombined, dried and concentrated under vacuum to provide 1.75 g (79% twosteps) of the title compound which is used in next step without furtherpurification or characterization.

Compound (9). To a solution of 7 (1.75 g, 4.74 mmol) in dichloromethane(25 mL) is added sequentially diisopropylethylamine (3.30 mL, 19 mmol),t-Boc-N-methyl-L-alanine (0.97 g, 4.74 mmol), and a solution of 0.45 MHOBt/HBTU in DMF (13 mL, 5.691 mmol). The mixture is stirred overnightat room temperature. The mixture is diluted with EtOAc (200 mL) andwashed sequentially with 1 M citric acid (50 mL), water (50 mL), aq.Sat. NaHCO₃ (50 mL) and brine (2×50 mL). The organic layer is dried andconcentrated under vacuum. The residue is dissolved in dichloromethane(20 mL), TFA (10 mL) is added and the mixture is stirred at roomtemperature for 3 hours. The mixture is concentrated and the residue isdissolved in dichloromethane (100 mL) and neutralized with saturatedsodium bicarbonate. The solution is extracted with dichloromethane (3×50mL). The organic extracts are combined, dried and concentrated undervacuum. The residue is purified by HPLC (C-18 silica gel, 20% CH₃CN/H₂Oin 0.5% TFA) to provide 1 g (36% two steps) of the title compound as TFAsalt. M+H⁺=455.39.

Example 2(S)—N—((S)-1-Cyclohexyl-2-{(2S,3R)-2-[(ethyl-phenethyl-amino)-methyl]-3-methyl-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide(23)

But-3-enyl-((S)-1-phenyl-ethyl)-amine (A): To a solution ofS-(−)-1-phenyl ethylamine (15.75 g, 130 mmol) in 150 mL of DMF at 0° C.is added K₂CO₃ (53.9 g, 390 mmol) in small portions. After stirring at0° C. for 10 min, 4-bromobutene (13.5 g, 100 mmol) is added dropwise andfollowed by NaI (58.5 g, 390 mmol) in small portions. The reactionmixture, a white suspension, is heated to 95° C. and stirredovernight/16 hrs. The solution is cooled to RT and diluted with 200 mLof ether, and washed with 3×100 ml of water. The organic layer is driedover Na₂SO₄ and concentrated. The crude product is purified bydistillation (65˜70° C. under high vacuum) to yield a colorless liquid(13.5 g, 76.7%). (NMR and MS data confirmed, U-4117-28-23).

[But-3-enyl-((S)-1-phenyl-ethyl)-amino]-acetic acid ethyl ester (B): Toa solution of But-3-enyl-((S)-1-phenyl-ethyl)-amine (6.37 g, 36.4 mmol)in 150 mL of DMF at 0° C. is added K₂CO₃ (10.0 g, 72.8 mmol) in smallportions. After stirring at 0° C. for 10 min, ethylbromoacetate (8.35 g,54.6 mmol) is added slowly. The reaction mixture, a white suspension, isstirred at r.t. overnight/16 hrs. The solution is diluted with 200 mL ofether, and washed with 3×100 ml of water. The crude product is purifiedby chromatography (hexane/CH₂Cl₂: 50/50) to give a pale liquid (8.5 g,94.5%). (NMR and MS data confirmed, U-4117-58).

(2S,3R)-3-But-3-enyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylicacid ethyl ester (C): To a solution of diisopropylamine (3.6 g, 35.7mmol) in THF (80 mL) at −40° C. is added BuLi (14.28 mL, 35.7 mmol, 2.5M in hexane) slowly. The solution is warmed to 0° C. and stirred for 30min to form an LDA solution. The LDA solution is cooled to −70° C. andadded to a solution of [But-3-enyl-((S)-1-phenyl-ethyl)-amino]-aceticacid ethyl ester (7.8 g, 29.8 mmol) in THF (80 mL) slowly at −70° C. Thelight yellowish reaction solution is stirred at −20° C. for 30 min tobecome a deep yellow solution, and then cooled to −70° C. To thesolution is added **ZnBr₂** (16.76 g, 74.5 mmol) in ether (50 mL)dropwise at −70° C. After stirring at RT for 1.5 hrs, the reactionsolution is cooled to 0° C. and added a solution of CuCN (3.47 g, 38.74mmol) and LiCl (3.29 g, 77.48 mmol) in THF (80 mL) slowly. Afterstirring at 0° C. for 10 min, allyl bromide (7.26 g, 60 mmol) is addeddropwise to the reaction solution, and warmed very slowly to r.t. Afterstirring overnight at r.t., the reaction is quenched by addition of 60mL of saturated NH₄Cl and extracted with 3×150 mL of ether. The combinedorganic layers is concentrated. The crude product is purified bychromatography (hexane/EtOAc:85/15) to give a colorless liquid (7.4 g,82.6%). (NMR and MS data confirmed, U-4117-40-19, U-4117-34-35).**ZnBr₂** is dried at 150° C. under high vacuum for 1 hour before used**

(2S,3R)-1-((2E,4Z)-(S)-1,2-Dimethyl-hexa-2,4-dienyl)-3-(3-oxo-propyl)pyrrolidine-2-carboxylicacid ethyl ester (D):(2S,3R)-3-But-3-enyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylicacid ethyl ester (1.0 g, 3.32 mmol) is dissolved in EtOH (10 mL) withHCl (0.5 mL, 37%), and cooled to −70° C. Ozone gas is bubbled though thesolution for about 10 min or until the solution is turned very lightblue color. The nitrogen gas is bubbled though the solution for 15 minto remove excess ozone in the solution. To the cool solution is added Zndust (0.43 g. 6.6 mmol) and HCl (0.5 mL, 37%), and stirred at r.t. for20 min. After filtration the solution is diluted with 50 mL of CH₂Cl₂and washed with saturated NaHCO₃ (10 mL) and 2×20 ml of water. Afterdried and concentrated, a colorless liquid (1.0 g) is obtained withoutfurther purification for next step reaction. (NMR and MS data confirmed,U-4117-51-30).

(2S,3R)-3-(3-Phenethylamino-propyl)-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylicacid ethyl ester (E): To a solution of(2S,3R)-1-((2E,4Z)-(S)-1,2-Dimethyl-hexa-2,4-dienyl)-3-(3-oxo-propyl)pyrrolidine-2-carboxylicacid ethyl ester (1 g, crude) in EtOH (10 mL) is added phenethylamine(0.44 g, 3.65 mmol) at r.t. After stirring at r.t. for 30 min, NaBH₃CN(0.3 g, 4.87 mmol) is added in one portion, After stirring at r.t. for1.5 Hrs, the reaction solution is diluted with 50 mL of ether and washedwith 20 mL of brine. The ether layer is concentrated and the crudeproduct is purified by chromatography (CH₂Cl₂/MeOH: 97/3) to give a paleliquid (405 mg, 30.0%). (NMR and MS data confirmed, U-4117-52-20).

(3aS,7aS)-6-Phenethyl-1-((S)-1-phenyl-ethyl)-octahydro-pyrrolo[2,3-c]pyridin-7-one(F):(2S,3R)-3-(3-Phenethylamino-propyl)-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylicacid ethyl ester (340 mg, 0.83 mmol) is dissolved in 20 mL ofMeOH/KOH/H₂O (10 mL/5 g/5 mL). After stirring at 80° C. for 2 hrs, thesolution is cooled to 0° C. and neutralized by addition of HCl (37%) topH=5. After concentration the crude product is dissolved in 1 mL ofCH₂Cl₂, and filtered through a short silica gel plug and eluted withCH₂Cl₂/MeOH (93/7) to give a pale glassy solid (250 mg, 78.9%) as theacid. (NMR and MS data confirmed, U-4117-60-22):

To a solution (0.05˜0.1 M) of acid (1 equivalent) in DMF at r.t. isadded diisopropylethylamine (5 equivalents). After stirring at r.t. for20 min, a solution (0.05˜0.1 M) of HOBT (1.2 equivalents) and HBTU (1.2equivalents) in DMF is added to the reaction mixture, and continued tobe stirred for 1.5 h (or monitored by TLC). The reaction solution isdiluted with ether (1×5˜10 times by volume of the solution), and washedwith water (twice ×3 by volume of the solution). The combined organicsolution is concentrated. The crude product is diluted with CH₂Cl₂ anddried over Na₂SO₄, and purified by chromatography (CH₂Cl₂/MeOH:97/3) togive pure product (70˜95% yield).

(NMR and MS data confirmed, U-4117-102).

Procedure for Compound F:

A solution of(2S,3R)-3-(2-Phenethylamino-ethyl)-1-((S)-1-phenyl-ethyl)-pyrrolidine-2carboxylic acid methyl ester (400 mg, 1.05 mmol) and 2-hydroxyl pyridine(100 mg, 1.05 mmol) in THF (10 mL) is stirred at 40° C. for 24 hrs. Thereaction is diluted with 50 mL of ether and washed with 2×120 mL ofwater. After dried and concentrated to give a pale liquid (350 mg, LC/MSshown a clean product only.) without further purification for next stepreaction.

(3aR,8aS)-7-Phenethyl-1-((S)-1-phenyl-ethyl)-decahydro-pyrrolo[2,3-c]azepine (G): To a solution (0.02M) of lactam (1 equivalent) in THF at−20° C. is added a solution (0.02M) of LiAlH₄ (2 equivalent) in THFslowly. After stirring at r.t. for 1.5 hrs, the solution is diluted withether (1×5 times by volume of the solution) and washed with water (twice2 times by volume of the solution), dried and concentrated. The crudeproduct is purified by Chromatography (CH₂Cl₂/MeOH:97/3) to give product(yield 70˜90%).

(NMR and MS data confirmed, U-4117-104).

(3aR,8aS)-7-Phenethyl-decahydro-pyrrolo[2,3-c]azepine (H): Asolution/suspension of reactant (<1 g) and Pd 10% on carbon (20% byweight) in MeOH (10 mL, with 2 drops of acetic acid) in a 1000 ml roundflask is vigorously stirred at r.t. under hydrogen gas (at atmospherepressure) from a balloon for 4˜8 hrs. After degassed by house vacuum for10 min, the reaction mixture is filtered to remove catalyst andconcentrated. The crude product is diluted with CH₂Cl₂/H₂O (8/2,reasonable amount) and neutralized with 10% NH₄OH to pH=7˜8. After driedand concentrated to give product (80%˜quantitative yield) withoutpurification for the next step reaction.

(NMR and MS data confirmed, U-4117-105).

(S)—N—((S)-1-Cyclohexyl-2-{(2S,3R)-2-[(ethyl-phenethyl-amino)-methyl]-3-methyl-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide(compound 23): Prepared from compound H following the proceduresestablished in Scheme 5.

Example 3

Diphenethylamine (D). To a solution of phenylacetaldehyde (6.0 g, 50mmol) and 2-phenylethylamine in THF (200 mL) is added sodiumtriacetoxy-borohydride drop wise. The solution is stirred under nitrogenovernight at room temperature. The solution is quenched with aq.saturated sodium bicarbonate (200 mL), and extracted with EtOAc (4×100mL). The organic extracts are combined, dried and concentrated undervacuum. The residue is purified by flash chromatography (silica gel;EtOAc/MeOH 9:1) to provide 1.25 g (11%) of the compound D as a clearoil. M+H⁺=226.10.

Diphenethyl-(S)-1-pyrrolidin-2-ylmethyl-amine (E). To a solution of(S)-2-Formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.0mmol) and D (1.125 g, 5.0 mmol) in THF (40 mL) is added sodiumtriacetoxyborohydride drop wise. The solution is stirred under nitrogenovernight at room temperature. The solution is quenched with aq.saturated sodium bicarbonate (40 mL). The mixture is extracted withEtOAc (4×50 mL). The organic extracts are combined, dried andconcentrated under vacuum. The residue is purified by flashchromatography (silica gel; Hexane/EtOAc 4:1) to provide a yellow oil.The yellow oil is dissolved in dichloromethane (20 mL), TFA (10 mL) isadded and the mixture is stirred at room temperature for 3 h. Themixture is concentrated and the residue is dissolved in dichloromethane(100 mL) and neutralized with saturated sodium bicarbonate. The solutionis extracted with dichloromethane (3×50 mL). The organic extracts arecombined, dried and concentrated under vacuum to provide 1.04 g (68% twosteps) of the title compound E which is used in the next step withoutfurther purification or characterization.

Compound (F). To a solution of t-Boc-L-cyclohexylglycine (0.868 g, 3.38mmol) in DMF (20 mL) is added diisopropylethylamine (1.83 mL, 16.9mmol). The mixture is stirred for 20 minutes at room temperature. Then asolution of E, HOBt (516 mg, 3.82 mmol) and HBTU (1.448 g, 3.82 mmol) inDMF (30 mL) is added. The mixture is stirred overnight at roomtemperature, and then diluted by ether (200 mL) and washed sequentiallywith aq. 1M citric acid (50 mL), water (50 mL), satd. aq. NaHCO₃ (50 mL)and brine (2×50 mL). The organic extract is dried and concentrated undervacuum. The residue is purified by flash chromatography (silica gel;Hexane/EtOAc 2:3) to provide a yellow oil. The yellow oil is dissolvedin dichloromethane (20 mL), TFA (10 mL) is added and the mixture isstirred at room temperature for 3 hours. The mixture is concentrated andthe residue is dissolved in dichloromethane (100 mL) and neutralizedwith saturated sodium bicarbonate. The solution is extracted withdichloromethane (3×50 mL). The organic extracts are combined, dried andconcentrated under vacuum to provide 780 mg (52% two steps) of the titlecompound F which is used in the next step without further purificationor characterization.

Compound 26. To a solution of t-Boc-N-methyl-L-alanine (354 mg, 1.75mmol) in DMF (20 mL) is added diisopropylethylamine (0.938 mL, 8.75mmol). The mixture is stirred for 20 minutes at room temperature. Then asolution of F, HOBt (267 mg, 1.98 mmol) and HBTU (751 mg, 1.98 mmol) inDMF (30 mL) is added. The mixture is stirred for 3 h at roomtemperature, and then diluted by ether (200 mL) and washed sequentiallywith 1 M citric acid (50 mL), water (50 mL), satd. aq. NaHCO₃ (50 mL)and brine (2×50 mL). The organic extract is dried and concentrated undervacuum. The residue is dissolved in dichloromethane (20 mL) and TFA (10mL) is added. The mixture is stirred at room temperature for 3 h andconcentrated. The resulting residue is dissolved in dichloromethane (100mL) and neutralized with saturated sodium bicarbonate. The solution isextracted with dichloromethane (3×50 mL). The organic extracts arecombined, dried and concentrated under vacuum. Portion of the residue ispurified by HPLC (C-18 silica gel, 30% CH₃CN/H₂O in 0.5% TFA) to provide120 mg of compound 26 as TFA salt. M+H⁺=533.47.

Example 4

Compound 32 is prepared as follows:

Compound I. Compounds G (122 mg, 1 mmole) and H (226 mg, 1 mmole) aredissolved in 5 mL DME. To this a mixture of 1 mL 2 N aq. Na₂CO₃ and 50mg Tetrakis is added. The resulting mixture is degassed for 5 minutes,stirred at 90° C. for 6 h, cooled down to room temperature, andconcentrated. The residue is purified by flash chromatography (ethylacetate/hexane) to provide I as an amber oil (204 mg, 90%). The crudeproduct is used directly in next reaction without further purificationor characterization.

Compound J. LAH (38 mg) is added to a solution of I (226 mg, 1 mmole) in5 mL THF 0° C. The temperature of the mixture is allowed to warm to roomtemperature and further stirred overnight. The reaction is quenched byfollowing the Fisher method, filtered and concentrated to provide J as acolorless oil (183 mg, 92%) and is used directly in next reactionwithout further purification or characterization.

Compound K. The suspension of compound J (198 mg, 1 mmole) and MnO₂ (870mg, 10 mmole) in 15 mL chloroform is stirred overnight. Filtering andconcentration yielded product K as a colorless oil (192 mg, 98%).

¹H NMR (CDCl₃) δ 9.96 (s, 1H), 7.72 (s, 2H), 7.47 (s, 2H), 7.15-7.35 (m,5H), 4.07 (s, 2H)

Compound L. A mixture of 3-chloropropylamine hydrochloride (140 mg, 1.1mmol), aldehyde K (196 mg, 1.0 mmol), and sodium carbonate (212 mg, 2mmol) in water (10 mL) is stirred overnight at room temperature. Theresulting solution is extracted with ethyl acetate (3×20 mL), separated,dried over Na₂SO₄ and evaporated in vacuum (15 Torr) to give anessentially pure oily residue (270 mg) which is used for the nextreaction without further purification. (M+H⁺ 272, calc. 272)

Compound M. Imine L (271 mg, 1 mmol) is added to a blue suspension oflithium powder (75 mg, 10 mmol) and a catalytic amount of DTBB (30 mg,0.10 mmol; 5% molar) in THF (5 mL) at −78° C. The resulting mixture isstirred for 2 h at same temperature. Reaction is quenched with water (20mL) allowing the temperature to rise to 20° C. The resulting solution ispurified by successively acid-base extraction with 2 M hydrochloric acid(3×15 mL) and 4 M sodium hydroxide (3×20 mL). The final solution isextracted with ethyl acetate (3×20 mL), separated, dried over Na₂SO₄ andevaporated to give pure compound M, (214 mg, 90%); (M+H⁺ 238, calc. 238)

Compound O. A mixture of compound M (237 mg, 1 mmole), compound N (257mg, 1 mmole), HBTU (460 mg, 1.2 mmole), HOBT (170 mg, 1.1 mmole), DIPEA(512 mg, 3 mmole) and 5 mL DMF is stirred overnight. The mixture isdiluted with ether (25 mL), washed with water, brine, dried over MgSO₄,filtered, and concentrated. The resulting residue is treated with 2 mLof CH₂Cl₂/TFA (1/1), stirred for 2 h, concentrated to provided product 0as a pale yellow solid (320 mg, 85%); (M+H⁺ 377, calc. 377).

Compound 32. A mixture of compound O (376 mg, 1 mmole),t-Boc-N-methylalanine P (203 mg, 1 mmole), HBTU (460 mg, 1.2 mmole),HOBT (170 mg, 1.1 mmole), DIPEA (512 mg, 3 mmole) and 5 mL DMF isstirred overnight. The mixture is diluted with ether (25 mL), washedwith water, brine, dried over MgSO₄, filtered, and concentrated. Theresulting residue is treated with 2 mL of CH₂Cl₂/TFA (1/1), stirred for2 h and concentrated under vacuum. Column chromatography providedcompound 32 as a pale yellow solid, (397 mg, 86%). (M+H⁺ 462, calc.462).

Example 5(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(indan-2-yloxymethyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide(34)

(S)-2-Methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butylester, (P). A flame dried flask charged with(S)-2-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g,5 mmol), dichloromethane (DCM) (20 mL) and triethylamine (0.70 mL, 5.2mmol) is cooled to 0° C. under N₂ is added a solution ofmethanesulfonychloride (0.38 mL, 5 mmol) in DCM (5 mL) dropwise over 10minutes. The reaction is stirred for 1 hour. After addition of DCM (100mL), the reaction mixture is washed with brine, dried and concentratedin vacuo. The residue is purified by chromatography on SiO₂ (5%EtOAc/Hexanes) to give 1.38 g of methanesulfonate ester (P) as a clearcolorless oil: LCMS (ES) 280.10 (MH⁺).

(S)-2-(Indan-2-yloxymethyl)-pyrrolidine-1-carboxylic acid tert-butylester, (Q). Sodium hydride (60%) (0.6 g, 14.4 mmol) is added to a flamedried flask charged with indan-2-ol (0.965 g, 7.2 mmol) andN,N′-dimethylformamide (DMF) (20 mL), cooled to 0° C. under N₂ andstirred for 30 minutes. A solution of(S)-2-Methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butylester (P) (1 g, 3.6 mmol) in DMF (5 mL) is added dropwise to thereaction mixture in such a manner as to maintain 0° C. The reaction isstirred at 60° C. for one hour, cooled to 0° C., quenched with brine,diluted with EtOAc, washed repeatedly with brine (6×), dried andconcentrated in vacuo. The residue is purified by chromatography on SiO₂(5% EtOAc/Hexanes) to give 0.20 g of indanyl ether (Q) as a clearcolorless oil: LCMS (ES) 340.17 (MNa+).

(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(indan-2-yloxymethyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide,(34).((S)-1-{(S)-1-Cyclohexyl-2-[(S)-2-(indan-2-yloxymethyl)-pyrrolidin-1-yl]-2-oxo-ethylcarbamoyl}-ethyl)-methyl-carbamicacid tert-butyl ester (Q) (0.54 g, 1 mmol) is dissolved in DCM (8 mL)and treated with trifluoroacetic acid (4 mL) for 45 minutes. Thereaction mixture is concentrated in vacuo, purified by preparativereverse-phase hplc to give 0.096 g of the methylamine (34) as a cleargum: LCMS (ES) 442.26 (MH⁺).

Example 6

1-Bromo-3-phenoxy-benzene (A) A mixture of dibromobenzene (3 g, 12.75mmol), phenol (1 g, 10.6 mmol), copper(I) oxide (152 mgs, 1 mmol), andcesium carbonate (3.46 g, 10.6 mmol) in 8 mL of NMP is heated at 195° C.for 20 minutes in a microwave. The heterogeneous mixture is filteredthrough a bed of Celite and the residue is washed with EtOAc (1×20 mL).The filtrate is diluted with 1N NaOH (200 mL) and extracted with EtOAc(3×100 mL). The organics were combined, dried over Na₂SO₄, filtered andconcentrated under reduced pressures to give crude product as a yellowoil which is purified by column chromatography (100% hexanes) to give1-bromo-3-phenoxy-benzene as a colorless oil (1.4 g, 53%). LCMS m/z 250(M+1).

5-(3-Phenoxy-phenyl)-3,4-dihydro-2H-pyrrole (B): To a cold solution(−78° C.) of 1-bromo-3-phenoxy-benzene (10.13 g, 40.6 mmol) in anhydrousTHF (100 mL) and under nitrogen is added n-BuLi (1.6M, 44.7 mmol, 27mL). The mixture is allowed to stir for 30 minutes before being added toa cold solution (−78° C.) of 1-(tert-Butoxycarbonyl)-2-pyrrolidionone inanhydrous THF (50 mL) under nitrogen via cannula. The resulting mixtureis allowed to warm to room temperature overnight before being quenchedwith water (200 mL) and extracted with EtOAc (3×100 mL). The organicswere collected, dried over Na₂SO₄, filtered and concentrated underreduced pressures. The residue is dissolved in CH₂Cl₂ (20 mL) and TFA(10 mL) is added with stirring. The mixture is stirred for 30 minutesand quenched over ice cold sat. NaHCO₃, extracted with CH₂Cl₂ (3×100 mL)and the organics were combined, dried over Na₂SO₄, filtered andconcentrated under reduced pressures. The residue is purified by silicagel column chromatography (20% EtOAc/Hexanes) to give5-(3-phenoxy-phenyl)-3,4-dihydro-2H-pyrrole as light yellow oil (6.1 g,63%). LCMS m/z 238 (M+1).

(S)-2-(3-Phenoxy-phenyl)-pyrrolidine (C): To oven dried round bottomflask is added S,S-EBTHITiF2 (100 mgs, 0.3 mmol) and diluted with THF (5mL). The flask is sealed and purged with argon. To the yellow solutionis added phenylsilane (4.6 mL, 37.5 mmol), pyrrolidine (100 uL, 1.1mmol), and anhydrous methanol (100 uL, 1.1 mmol). The resulting yellowmixture is stirred for 45 minutes until green color persisted. Asolution of 5-(3-phenoxy-phenyl)-3,4-dihydro-2H-pyrrole (1.2 g, 5.05mmol) in THF (2 mL) is added to the catalyst and the mixture is stirredfor 8 hrs. The reaction is carefully quenched with 10% HCl (100 mL)until gas evolution subsided and the pH˜2. The mixture is diluted withEtOAc (100 mL) and the aqueous layer is removed, neutralized with 3MNaOH (50 mL) until basic and extracted with EtOAc (3×100 mL). Theorganics were combined, dried over Na₂SO₄, filtered and concentratedunder reduced pressures. The solid residue is purified by silica gelcolumn chromatography (100% EtOAc) to give(S)-2-(3-phenoxy-phenyl)-pyrrolidine as a yellow solid (580 mgs, 48%).LCMS m/z 240.1 (M+1).

{(S)-1-Cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethyl}-carbamicacid tert-butyl ester (D): (S)-2-(3-phenoxy-phenyl)-pyrrolidine (1.2 g,5.02 mmol) is added to a solution of Boc-L-α-cyclohexylglycine (1.42 g,5.2 mmol), HOBt (1.0 g, 7.53 mmol) and HBTU (2.86 g, 7.53 mmol) in 10 mLof DMF. Hunig's base (3.6 MI, 20 mmol) is added and the mixture isstirred for 30 minutes. The mixture is diluted with brine (20 mL) andextracted with EtOAc (3×10 mL). The organics were combined, dried overNa₂SO₄, filtered, concentrated under reduced pressures and purified bysilica gel column chromatography (20% EtOAc/Hexanes) to give{(S)-1-cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolidine-1-yl]-ethyl}-cabamicacid tert-butyl ester as a white powder (1.65 g, 66%). LCMS m/z 479.2(M+1).

(S)-2-Amino-2-cyclohexyl-1-[(S)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethanone(E): To a solution of{(S)-1-cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolidine-1-yl]-ethyl}-carbamicacid tert-butyl ester in CH₂Cl₂ (20 mL) is added TFA (10 mL) and themixture is stirred for 30 minutes. The mixture is concentrated underreduced pressures to give(S)-2-amino-2-cyclohexyl-1-[(S)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethanoneas a TFA salt quantitatively (1.65 g). LCMS m/z 379 (M+1).

((S)-1-{(S)-1-Cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethylcarbamoyl}-ethyl)-methyl-carbamicacid tert-butyl ester (F): To a solution of Boc-N-methyl-L-alanine (771mgs, 3.79 mmol), HOBt (700 mgs, 5.17 mmol), and HBTU (2.0 g, 5.17 mmol)in DMF (10 mL) is added(S)-2-amino-2-cyclohexyl-1-[(S)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethanoneand DIPEA (3 mL, 17.25 mmol). The mixture is stirred for 30 minutes anddiluted with brine (20 mL) and extracted with EtOAc (3×10 mL). Theorganics were combined, dried over Na₂SO₄, filtered, concentrated underreduced pressures and purified by silica gel column chromatography (50%EtOAc/Hexanes) to give the product ((S)1-{(S)-1-cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolodin-1-yl]-ethylcarbamoyl}-ethyl)-methyl-carbamicacid tert-butyl ester as a white powder (1.3 g, 84%). LCMS m/z 564(M+1).

(S)—N-{(S)-1-Cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethyl}-2-methylamino-propionamide(45): To a solution of ((S)1-{(S)-1-cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolodin-1-yl]-ethylcarbamoyl}-ethyl)-methyl-carbamicacid tert-butyl ester (450 mgs, 0.79 mmol) in CH₂Cl₂ (20 mL) is addedTFA (10 mL) and stirred for 30 minutes. The mixture is concentratedunder reduced pressures and purified by reverse phase columnchromatography to give the product as a TFA salt (370 mgs, 82%). LCMSm/z 464.1 (M+1).

Example 7

(S)-2-(1H-Tetrazol-5-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester(A). To a solution of (S)-2-Cyano-pyrrolidine-1-carboxylic acidtert-butyl ester (500 mg, 2.55 mmol) in N,N-dimethyl-formamide (20 mL)is added sodium azide (174 mg, 2.68 mmol) and ammonium chloride (150 mg,2.81 mmol). The solution is stirred at 93° C. over night. The solutionis poured into 5% citric acid solution with ice, and the mixture isextracted with EtOAc. The organic extract is washed with brine, driedand concentrated under vacuum. The crude oil is used directly in thenext step without further purification. M+H⁺=240.

(S)-2-(2-Benzyl-2H-tetrazol-5-yl)-pyrrolidine-1-carboxylic acidtert-butyl ester (B). To a solution of crude compound A inN,N-dimethyl-formamide (5 mL) is added K₂CO₃ (1.16 g, 8.4 mmol) andbenzyl bromide (665 uL, 5.6 mmol). The solution is stirred at roomtemperature for 1 hr. The mixture is diluted with EtOAc and washed withbrine. The organic layer is dried and concentrated under vacuum. Theresidue is purified by flash column chromatography (Hexanes/EtOAc) toprovide 404 mg of the title compound M+H⁺=330, and 401 mg of the otherregion isomer (S)-2-(1-Benzyl-1H-tetrazol-5-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (C). M+H⁺=330. Combined yield is 87% for 2 steps.

2-Benzyl-5-(S)-pyrrolidine-2-yl-2H-tetrazole (D). To a solution ofcompound B in DCM (5 mL) is added triethylsilane (479 uL, 3.0 mmol) andthen TFA (5 mL). The solution is stirred at room temperature for 1 hrand dried under vacuum. The crude oil is used directly in the next stepwithout further purification. M+H⁺=230.

{2-[(S)-2-(2-Benzyl-2H-tetrazol-5-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-carbamicacid tert-butyl ester (E). To a solution of(S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (123.8 mg, 0.48mmol) in DMA (5 mL) is added HBTU (248.8 mg, 0.656 mmol), HOBt (88.6 mg,0.656 mmol) and diisopropylethylamine (305 uL, 1.75 mmol). The mixtureis stirred at room temperature for 5 minutes. A solution of compound Din DCM (5 mL) is added to the above mixture at 0° C. The reactionmixture is stirred at room temperature for 1 hour and concentrated undervacuum. The residue is diluted with EtOAc. The organic is washed withbrine, citric acid (5%), brine, NaHCO₃(Sat.) and brine. The organiclayer is then dried and concentrated under vacuum. The residue ispurified by flash column chromatography (Hexanes/EtOAc) to provide thetitle compound 190 mg (92%). M+H⁺=369.

2-Amino-1-[(S)-2-(2-Benzyl-2H-tetrazol-5-yl)-pyrrolidin-1-yl]-2-cyclohexylethanone;compound with trifluoro-acetic acid (F). To a solution of compound E inDCM (4 mL) is added TFA (4 mL) at 0° C. The solution is stirred at roomtemperature for 1 hr and dried under vacuum. The crude oil is useddirectly in the next step without further purification. M+H⁺=369.

((S)-1-{2-[(S)-2-(2-Benzyl-2H-tetrazol-5-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethylcarbamoyl}-propyl)-methyl-carbamicacid tert-butyl ester (G). To a solution of(S)-2-(tert-butoxycarbonyl-methyl-amino)-butyric acid (53.0 mg, 0.24mmol) in DMA (2 mL) is added HBTU (125.0 mg, 0.33 mmol), HOBt (44.6 mg,0.33 mmol) and diisopropylethylamine (192 uL, 1.1 mmol). The mixture isstirred at room temperature for 5 minutes. A solution of compound F inDCM (2 mL) is added to the above mixture at 0° C. The reaction mixtureis stirred at room temperature for 1 hour and concentrated under vacuum.The residue is diluted with EtOAc. The organic is washed with brine,citric acid (5%), brine, NaHCO₃(Sat.) and brine. The organic layer isthen dried and concentrated under vacuum. The crude oil is used directlyin the next step without further purification. M+H⁺=554.

(S)—N-{2-[(S)-2-(2-Benzyl-2H-tetrazol-5-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-butyramide;compound with trifluoro-acetic acid (50). To a solution of compound G inDCM (2 mL) is added TFA (2 mL) at 0° C. The solution is stirred at roomtemperature for 1 hr and dried under vacuum. The crude oil is purifiedby HPLC to provide the title compound. M+H⁺=467.

Example 8

2-(Benzyloxyimino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester(A). To a solution of benzylhydroxylamine (2.64 g, 16.56 mmole) in drypyridine (20 ml) is added 2-formyl-pyrrolidine-1-carboxylic acidtert-butyl ester (3.30 g, 16.56 mmole). The solution is stirred forthree hours at room temperature. The reaction solution is quenched withwater and extracted with dichloromethane. The organic layer is combined,dried, and concentrated under vacuum. The residue is purified by flashchromatography (silica gel; from 50% to 50% of ethyl acetate in hexane)to provide 4.9 g (98%) of the title compound. M+H⁺-Boc=205.1.

Pyrrolidine-2-carbaldehyde-O-benzyl-oxime (B). The solution of2-(benzyloxyimino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester(1.50 g, 4.92 mmole) and TFA (10 ml) in dichloromethane (10 ml) isstirred for 2 hours at room temperature. Solvent is removed. The crudeproduct is carried to next step without further purification. M+H⁺=205.1

{(S)-2-[Benzyloxylimino-methyl-pyrrolidine-1-yl]-1-cyclohexyl-2-oxo-ethyl}-carbamicacid tert-butyl ester (C). The solution of boc-L-α-cyclohexylglycine(1.27 g, 4.92 mmole), 1-hydroxylbenzotriazole (0.99 g, 7.38 mmole),diisopropylethylamine (2.54 g, 19.68 mmole), andO-benzotriazole-N,N,N,N-tetramethyl-urounium hexafluorophosphate (2.80g, 7.38 mmole) in dichloromethane (30 ml) is stirred for 15 minutes atroom temperature. A solution ofpyrrolidine-2-carbaldehyde-O-benzyl-oxime (˜1.00 g, 0.49 mmole) indichloromethane is added. The reaction solution is stirred for threehours at room temperature and then quenched with saturated NaHCO₃aqueous., extracted with dichloromethane. The organic layer is combined,dried, and concentrated under vacuum. The residue is purified by flashchromatography (silica gel; from 20% to 70% of ethyl acetate in hexane)to provide 1.81 g (83% over 2 steps) of the title compound. M+H⁺=444.2

1-((S)-2-Amino-2-cyclohexyl-acetyl)-pyrrolidine-2-Carbaldehyde-O-benzyl-oxime(D). The solution of{(S)-2-[benzyloxylimino-methyl-pyrrolidine-1-yl]-1-cyclohexyl-2-oxo-ethyl}-carbamicacid tert-butyl ester (1.76 g, 3.97 mmole) and TFA (10 ml) indichloromethane (20 ml) is stirred for a hour. Solvent is removed undervacuum. The residue is carried to next step without furtherpurification. M+H⁺=344.2

((S)-1-{(S)-2-[2-(Benzyloxyimino-methyl)-pyrrolidine-1-yl]-1-cyclohexyl-2-oxo-ethylcarbamoyl}-ethyl)-methyl-carbamicacid tert-butyl ester (E). The solution of Boc-L-α-cyclohexylglycine(0.81 g, 3.87 mmole), 1-hydroxylbenzotriazole (0.81 g, 5.95 mmole),diisopropylethylamine (2.05 g, 15.88 mmole), andO-benzotriazole-N,N,N,N-tetramethyl-urounium hexafluorophosphate (2.35g, 5.95 mmole) in dichloromethane is stirred for 15 minutes at roomtemperature. A solution of1-((S)-2-amino-2-cyclohexyl-acetyl)-pyrrolidine-2-carbaldehyde-O-benzyl-oxime(˜1.40 g, 3.97 mmole) in dichloromethane is added. The reaction solutionis stirred for three hours at room temperature and then quenched withsaturated NaHCO₃ aqueous and extracted with dichloromethane. The organiclayer is combined, dried, and concentrated under vacuum. The residue iscarried to next step without further purification. M+H⁺=529.4.

(S)—N-{2-[2-(Benzyloxyimino-methyl-pyrrolidine-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide(8). The solution of((S)-1-{(S)-2-[2-(benzyloxyimino-methyl)-pyrrolidine-1-yl]-1-cyclohexyl-2-oxo-ethylcarbamoyl}-ethyl)-methyl-carbamicacid tert-butyl ester (˜2.10 g, 3.97 mmole) and TFA (20 ml) indichloromethane (40 ml) is stirred for a hour. Solvent is removed undervacuum. 1.36 g of crude product is obtained. The crude product (0.66 g)is purified by HPLC (C18 silica gel, from 10% to 70% of CH₃CN/H₂O in0.1% TFA) to provide 0.058 g of the title compound as TFA salt ofisomeric mixtures. M+H⁺=429.4.

Examples 9-78

The following compounds are prepared by methods analogous to thosedescribed herein utilizing analogous starting materials:

Compound Structure Example Number

Example 9MS ESI 455.34 (M + H)⁺

Example 10MS ESI 429.46 (M + H)⁺

Example 11MS ESI 429.46 (M + H)⁺

Example 12MS ESI 443.46 (M + H)⁺

Example 13MS ESI 443.47 (M + H)⁺

Example 14MS ESI 443.48 (M + H)⁺

Example 15MS ESI 457.27 (M + H)⁺

Example 16MS ESI 469.23 (M + H)⁺

Example 17MS ESI 415.26 (M + H)⁺

Example 18MS ESI 443.19 (M + H)⁺

Example 19MS ESI 443.19 (M + H)⁺

Example 20MS ESI 535.33 (M + H)⁺

Example 21MS ESI 497.33 (M + H)⁺

Example 22MS ESI 497.35 (M + H)⁺

Example 23MS ESI 469.36 (M + H)⁺

Example 24MS ESI 457.6 (M + H)⁺

Example 25MS ESI 481.7 (M + H)⁺

Example 26MS ESI 533.5 (M + H)⁺

Example 27MS ESI 457.43 (M + H)⁺

Example 28MS ESI 443.23 (M + H)⁺

Example 29MS ESI 442.65 (M + H)⁺

Example 30MS ESI 428.62 (M + H)⁺

Example 31MS ESI 414.30 (M + H)⁺

Example 32MS ESI 462.0 (M + H)⁺

Example 33MS ESI 422.1 (M + H)⁺

Example 34MS ESI 442.26 (M + H)⁺

Example 35MS ESI 430.28 (M + H)⁺

Example 36MS ESI 446.6 (M + H)⁺

Example 37MS ESI 462.6 (M + H)⁺

Example 38MS ESI 478.7 (M + H)⁺

Example 39MS ESI 462.3 (M + H)⁺

Example 40MS ESI 462.3 (M + H)

Example 41MS ESI 437.3 (M + H)⁺

Example 42MS ESI 477.3 (M + H)⁺

Example 43MS ESI 477.3 (M + H)⁺

Example 44MS ESI 464.3 (M + H)⁺

Example 45MS ESI 464.3 (M + H)⁺

Example 46MS ESI 480.3 (M + H)⁺

Example 47MS ESI 480.3 (M + H)⁺

Example 48MS ESI 512.0 (M + H)⁺

Example 49MS ESI 454.3 (M + H)⁺

Example 50MS ESI 468.3 (M + H)⁺

Example 51MS ESI 454.3 (M + H)⁺

Example 52MS ESI 468.3 (M + H)⁺

Example 53MS ESI 439 (M + H)⁺

Example 54MS ESI 453 (M + H)⁺

Example 55MS ESI 469.3 (M + H)⁺

Example 56MS ESI 523.2 (M + H)⁺

Example 57MS ESI 511 (M + H)⁺

Example 58MS ESI 485 (M + H)⁺

Example 59MS ESI 509 (M + H)⁺

Example 60MS ESI 826 (M + H)⁺

Example 61MS ESI 471.3 (M + H)⁺

Example 62MS ESI 469.4 (M + H)⁺

Example 63MS ESI 415.3 (M + H)⁺

Example 64MS ESI 443.4 (M + H)⁺

Example 65MS ESI 429.4 (M + H)⁺

Example 66MS ESI 429.4 (M + H)⁺

Example 67MS ESI 539.3 (M + H)⁺

Example 68MS ESI 539.3 (M + H)⁺

Example 69MS ESI 455.3 (M + H)⁺

Example 70MS ESI 455.3 (M + H)⁺

Example 71MS ESI 441.3 (M + H)⁺

Example 72MS ESI 469.3 (M + H)⁺

Example 73MS ESI 469.3 (M + H)⁺

Example 74MS ESI 455.3 (M + H)⁺

Example 75MS ESI 455.3 (M + H)⁺

Example 76MS ESI 469.3 (M + H)⁺

Example 77MS ESI 512.2 (M + H)⁺

Example 78MS ESI 496.3 (M + H)⁺

Additional compounds within the scope of Formula I include:

Example 79MS ESI 496 (M + H)⁺

Example 80MS ESI 498 (M + H)

Example 81MS ESI 476 (M + H)⁺

Example 82MS ESI 520 (M + H)⁺

Example 83MS ESI 424 (M + H)⁺

Example 84MS ESI 424 (M + H)⁺

Example 85MS ESI 424 (M + H)⁺

Example 86MS ESI 396 (M + H)⁺

Example 87MS ESI 410 (M + H)⁺

Example 88MS ESI 438 (M + H)⁺

Example 89MS ESI 450 (M + H)+

Example 90MS ESI 464 (M + H)⁺

Example 91MS ESI 478 (M + H)⁺

Example 92MS ESI 438 (M + H)+

Example 93MS ESI 472 (M + H)+

Example 94MS ESI 465 (M + H)⁺

Example 95MS ESI 465 (M + H)⁺

Example 96MS ESI 465 (M + H)⁺

Example 97MS ESI 466 (M + H)⁺

Example 98MS ESI 465 (M + H)⁺

Example 99MS ESI 529 (M + H)⁺

Example 100MS ESI 463 (M + H)⁺

Example 101MS ESI 409 (M + H)⁺

Example 102MS ESI 423 (M + H)⁺

Example 103MS ESI 451 (M + H)⁺

Example 104MS ESI 477 (M + H)⁺

Example 105MS ESI 491 (M + H)⁺

Example 106MS ESI 485 (M + H)⁺

Example 107MS ESI 451 (M + H)⁺

Example 108MS ESI 463 (M + H)⁺

Example 109MS ESI 541 (M + H)⁺

Example 110MS ESI 491 (M + H)⁺

Example 111MS ESI 507 (M + H)⁺

Example 112MS ESI 531 (M + H)⁺

Example 113MS ESI 497 (M + H)⁺

Example 114MS ESI 496 (M + H)⁺

Example 115MS ESI 478 (M + H)⁺

Example 116MS ESI 496 (M + H)⁺

Example 117MS ESI 512 (M + H)⁺

Example 118MS ESI 514 (M + H)⁺

Example 119MS ESI 479 (M + H)⁺

Example 120MS ESI 478 (M + H)⁺

Example 121MS ESI 479 (M + H)⁺

Example 122MS ESI 496 (M + H)⁺

Example 123MS ESI 453 (M + H)⁺

Example 124MS ESI 452 (M + H)⁺

Example 125MS ESI 467 (M + H)⁺

Example 126MS ESI 481 (M + H)⁺

Example 127MS ESI 453 (M + H)

Example 128MS ESI 511 (M + H)⁺

Example 129MS ESI 573 (M + H)⁺

Example 130MS ESI 483 (M + H)⁺

Example 131MS ESI 468 (M + H)⁺

Example 132MS ESI 454 (M + H)⁺

Example 133MS ESI 451 (M + H)⁺

Example 134MS ESI 451 (M + H)

Example 135MS ESI 510 (M + H)⁺

Example 136MS ESI 465 (M + H)

Example 137MS ESI 464 (M + H)⁺

Example 138MS ESI 452 (M + H)⁺

Example 139MS ESI 454 (M + H)⁺

Example 140MS ESI 535 (M + H)⁺

Example 141MS ESI 405 (M + H)⁺

Example 142MS ESI 473 (M + H)⁺

Example 143MS ESI 513 (M + H)⁺

Example 144MS ESI 527 (M + H)⁺

Example 145MS ESI 541 (M + H)⁺

Example 146MS ESI 547 (M + H)⁺

Example 147MS ESI 575 (M + H)⁺

Example 148MS ESI 463 (M + H)⁺

Example 149MS ESI 505 (M + H)⁺

Example 150MS ESI 505 (M + H)⁺

Example 151MS ESI 483 (M + H)⁺

Example 152MS ESI 469 (M + H)⁺

Example 153MS ESI 483 (M + H)⁺

Example 154MS ESI 463 (M + H)⁺

Example 155MS ESI 447 (M + H)⁺

Example 156MS ESI 447 (M + H)⁺

Example 157MS ESI 448 (M + H)⁺

Example 158MS ESI 446 (M + H)⁺

Example 159MS ESI 447 (M + H)⁺

Example 160MS ESI 441 (M + H)⁺

Example 161MS ESI 455 (M + H)⁺

Example 162MS ESI 469 (M + H)⁺

Example 163MS ESI 467 (M + H)⁺

Example 164MS ESI 481 (M + H)⁺

Example 165MS ESI 487 (M + H)⁺

Example 166MS ESI 387 (M + H)⁺

Example 167MS ESI 401 (M + H)⁺

Example 168MS ESI 415 (M + H)⁺

Example 169MS ESI 429 (M + H)⁺

Example 170MS ESI 449 (M + H)⁺

Example 171MS ESI 463 (M + H)⁺

Example 172MS ESI 441 (M + H)⁺

Example 173MS ESI 413 (M + H)⁺

Example 174MS ESI 455 (M + H)⁺

Example 175MS ESI 469 (M + H)⁺

Example 176MS ESI 427 (M + H)⁺

Example 177MS ESI 443 (M + H)⁺

Example 178MS ESI 469 (M + H)⁺

Example 179MS ESI 469 (M + H)⁺

Example 180MS ESI 401 (M + H)⁺

Example 181MS ESI 401 (M + H)⁺

Example 182MS ESI 415 (M + H)⁺

Example 183MS ESI 415 (M + H)⁺

Example 184MS ESI 429 (M + H)⁺

Example 185MS ESI 443 (M + H)⁺

Example 186MS ESI 463 (M + H)⁺

Example 187MS ESI 477 (M + H)⁺

Example 188MS ESI 455 (M + H)⁺

Example 189MS ESI 427 (M + H)⁺

Example 190MS ESI 469 (M + H)⁺

Example 191MS ESI 483 (M + H)⁺

Example 192MS ESI 441 (M + H)⁺

Example 193MS ESI 457 (M + H)⁺

Example 194MS ESI 415 (M + H)⁺

Example 195(S)—N—[(S)-1-Cyclohexyl-2-((R)-2-{6-[(2-fluoro-phenyl)-methyl-amino]-pyridin-2-yl}-pyrrolidin-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide(78)

4,4,N-Trimethoxy-N-methyl-butyramide (1)

To a solution of methyl 4,4-dimethoxy-butyrate (4.99 g, 30.8 mmol) andN,O-dimethylhydroxylamine HCl (4.65 g, 47.68 mmol) in 60 mL of THF at−20° C., is added isopropylmagnesiumchloride (46 mL, 92.28 mmol, 2.0M inTHF) maintaining the temperature below −20° C. After stirring at −10° C.for 30 min, the reaction mixture is quenched with 50 mL of water andextracted with 3×80 mL of EtOAc. The combined organic layers is driedover Na₂SO₄ and filtered through a short silica gel pluge. The solutionis concentrated to give 4,4,N-Trimethoxy-N-methylbutyramide (5.9 g, 99%)as pale liquid. M/Z=191.0

N-[1-Eth-(Z)-ylidene-5,5-dimethoxy-2-oxo-pentyl]-acrylimidoyl bromide(2)

To a suspension of 2,6-dibromopyridine (8.1 g, 34.03 mmol) in 80 mL ofether at −70° C., is added BuLi (12.3 mL, 26.17 mmol, 2.5 M in Hexane)in on portion. After stirring at −70° C. for 5 min,4,4,N-Trimethoxy-N-methyl-butyramide (5.0 g, 26.17 mmol) is added to thesolution dropwise. After stirring at −70° C. for 1.5 hr, the reactionmixture is quenched with 120 mL of water and extracted with 3×130 mL ofEtOAc. The combined organic layers is concentrated and purified bychromatography (Hexane/EtOAc:70/30) to giveN-[1-Eth-(Z)-ylidene-5,5-dimethoxy-2-oxo-pentyl]-acrylimidoyl bromide(5.96 g, 60.5%) as light yellow liquid. M/Z=288.0

N-[1-Eth-(Z)-ylidene-2,5-dioxo-pentyl]-acrylimidoyl bromide (3)

To a solution ofN-[1-Eth-(Z)-ylidene-5,5-dimethoxy-2-oxo-pentyl]acrylimidoyl bromide(7.0 g, 28.9 mmol) in a solution of acetone (30 mL) and water (1.5 mL)at room temperature, is added Amberlyse-15 (20 g). After mechanicalshacking for 3 hr at room temperature, the reaction mixture is filtered.The resin beads were washed with acetone (contain 10% of Et₃N). Thecombined organic layers were concentrated and purified by chromatography(Hexane/EtOAc:70/30) to yieldN-[1-Eth-(Z)-ylidene-2,5-dioxo-pentyl]-acrylimidoyl bromide (5.18 g,88.1%) as light yellow liquid. M/Z=421, 243.9 [M+1]

2-Bromo-6-[(S)-1-((R)-1-phenyl-ethyl)-pyrrolidin-2-yl]-pyridine (4)

To a solution of N-[1-Eth-(Z)-ylidene-2,5-dioxo-pentyl]-acrylimidoylbromide (1.0 g, 4.1 mmol) and R(+)-α-methylbenzylamine (0.5 g, 4.1 mmol)in 17 mL of CH₂Cl₂ at 70° C., is added acetic acid (0.6 mL) and sodiumtriacetoxyborohydride (1.74 g, 8.2 mmol). After stirring at −70° C. for40 min, the dry ice bath is removed, and the reaction solution is warmedto room temperature. After stirring at room temperature overnight, thereaction mixture is quenched with 20 mL of water and extracted with 3×30mL of CH₂Cl₂. The combined organic layers were concentrated and purifiedby chromatography (Hexane/EtOAc:70/30) to yield2-Bromo-6-[(S)-1-((R)-1-phenyl-ethyl)-pyrrolidin-2-yl]-pyridine (0.86 g,62.9%) as light yellow liquid. M/Z=332.7 [M+1]

(Z)-N-(2-Fluoro-phenyl)-N-methyl-N′-[1-[(S)-1-((R)-1-phenyl-ethyl)-pyrrolidin-2-yl]-prop-2-en-(E)-ylidene]-propenamidine(5)

To a solution of2-Bromo-6-[(S)-1-((R)-1-phenyl-ethyl)-pyrrolidin-2-yl]-pyridine (86.5mg, 2.57 mmol), 2-fluoro-methylaniline (64.7 mg, 5.14 mmol) and2-(di-cyclohexylphosphino)-bipheny (38.5 mg, 0.13 mmol) in 20 mL oftoluene at room temperature, were added Pd₂(dba)₃ (117.6 mg, 0.13 mmol).The reaction mixture is stirred at 80° C. for 2 hrs, and then cooled toroom temperature. The reaction mixture is filtered through celite, andthe filtrate is diluted with 50 mL of EtOAc and washed with 2×50 mL ofwater. The combined organic layers were concentrated and purified bychromatography (CH₂Cl₂/MeOH: 97/3) to give(Z)-N-(2-Fluoro-phenyl)-N-methyl-N′-[1-[(S)-1-((R)-1-phenyl-ethyl)-pyrrolidin-2-yl]-prop-2-en-(E)-ylidene]-propenamidine(870 mg, 90.3%) as pale solid. M/Z=376.0 [M+1]

(Z)-N-(2-Fluoro-phenyl)-N-methyl-N′-[1-[(S)-1-((R)-1-phenyl-ethyl)-pyrrolidin-2-yl]-prop-2-en-(E)-ylidene]-propenamidine(6)

(Z)-N-(2-Fluoro-phenyl)-N-methyl-N′-[1-[(S)-1-((R)-1-phenyl-ethyl)-pyrrolidin-2-yl]-prop-2-en-(E)-ylidene]-propenamidine(500 mg, 1.33 mmol) is dissolved in 10 mL of MeOH in a 500 mL roundbottle flask with 300 mg of Pd/C. The reaction mixture is stirred underH₂ gas (1 atm) from a balloon for 24 hours. After degassing undervacuum, the reaction mixture is filtered to remove catalyst. The crudeproduct is purified by reverse phase HPLC to give(Z)-N-(2-Fluoro-phenyl)-N-methyl-N′-[1-[(S)-1-((R)-1-phenyl-ethyl)-pyrrolidin-2-yl]-prop-2-en-(E)-ylidene]-propenamidine(200 mg, 55.4%) as yellow oil. M/Z=272.07 [M+1]

[(S)-1-Cyclohexyl-2-((S)-2-{1-[(E)-(Z)-N-(2-fluoro-phenyl)-N-methyl-1-imioxo-propenylimino]-allyl}-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamicacid tert-butyl ester (7)

To a solution of Boc-L-a-cyclohexyglycine (204 mg, 0.79 mmol) in 5 mL ofDMF at room temperature, is added diisopropylethylamine (0.58 mL, 3.3mmol) slowly. After stirring at room temperature for 20 minutes, asolution of HOBT (116 mg, 0.86 mmol) and HBTU (325 mg, 0.86 mmol) in DMF(5 mL) is added to the reaction mixture, and the solution is transferredto another flask contained(Z)-N-(2-Fluoro-phenyl)-N-methyl-N′-[(S)-1-pyrrolidin-2-yl-prop-2-en-(E)-ylidene]-propenamidine(180 mg, 0.66 mmol). After stirring for 1 hr, the reaction solution isdiluted with EtOAc (50 mL), and washed with water (3×20 mL). Thecombined organic layers is concentrated. The crude product is dilutedwith CH₂Cl₂ (10 mL) and dried over Na₂SO₄, and purified bychromatography (CH₂Cl₂/MeOH:97/3) to give[(S)-1-Cyclohexyl-2-((S)-2-{1-[(E)-(Z)-N-(2-fluoro-phenyl)-N-methyl-1-imioxo-propenylimino]-allyl}-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamicacid tert-butyl ester (320 mg, 94.5%) as pale gum. M/Z=511.14[M+1]

(Z)-N′-[1-[(S)-1-((S)-2-Amino-2-cyclohexyl-acetyl)-pyrrolidin-2-yl]-prop-2-en-(E)-ylidene]-N-(2-fluoro-phenyl)-N-methyl-propenamidine(8)

To a solution of[(S)-1-Cyclohexyl-2-((S)-2-{1-[(E)-(Z)-N-(2-fluoro-phenyl)-N-methyl-1-imioxo-propenylimino]-allyl}-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamicacid tert-butyl ester (320 mg, 0.63 mmol) in CH₂Cl₂ (3 mL) at −20° C. isadded TFA (5 ML, pre-cooled to −20° C.) slowly. After stirring at 0° C.for 30 min, the reaction mixture is concentrated to remove most of TFA.The residue is dissolved in 20 mL of CH₂Cl₂, and neutralized with 10%NH₄OH to PH=8. The solution is dried over Na₂SO₄ and concentrated togive(Z)-N′-[1-[(S)-1-((S)-2-Amino-2-cyclohexyl-acetyl)-pyrrolidin-2-yl]-prop-2-en-(E)-ylidene]-N-(2-fluoro-phenyl)-N-methyl-propenamidine(260 mg, quantitative) as pale gum without further purification for nextstep reaction. M/Z=411.2 [M+1]

{(S)-1-[(S)-1-Cyclohexyl-2-((S)-2-{6-[(2-fluoro-phenyl)-methyl-amino]-pyridin-2-yl}-pyrrolidin-1-yl)-2-oxo-ethylcarbamoyl]-ethyl}-methyl-carbamicacid tert-butyl ester (9)

To a solution of Boc-N-methyl-L-a-alanine (155 mg, 0.76 mmol) in 5 mL ofDMF at room temperature, is added diisopropylethylamine (0.58 mL, 3.3mmol) slowly. After stirring at room temperature for 20 minutes, asolution of HOBT (111 mg, 0.82 mmol) and HBTU (311 mg, 0.82 mmol) in DMF(5 mL) is added to the reaction mixture, and the solution is transferredto another flask contained(Z)-N′-[1-[(S)-1-((S)-2-Amino-2-cyclohexyl-acetyl)-pyrrolidin-2-yl]-prop-2-en-(E)-ylidene]-N-(2-fluoro-phenyl)-N-methyl-propenamidine(260 mg, 0.63 mmol). After stirring for 1 hr, the reaction solution isdiluted with EtOAc (50 mL), and washed with water (3×20 mL). Thecombined organic layers is concentrated. The crude product is dilutedwith CH₂Cl₂ (10 mL) and dried over Na₂SO₄, and purified bychromatography (CH₂Cl₂/MeOH:97/3) to give{(S)-1-[(S)-1-Cyclohexyl-2-((S)-2-{6-[(2-fluoro-phenyl)-methyl-amino]-pyridin-2-yl}-pyrrolidin-1-yl)-2-oxo-ethylcarbamoyl]-ethyl}-methyl-carbamicacid tert-butyl ester (300 mg, 79.5%) as pale gum. M/Z=596.2[M+1]

(S)—N—[(S)-1-Cyclohexyl-2-((S)-2-{6-[(2-fluoro-phenyl)-methyl-amino]-pyridin-2-yl}-pyrrolidin-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide(78)

To a solution of give{(S)-1-[(S)-1-Cyclohexyl-2-((S)-2-{6-[(2-fluoro-phenyl)-methyl-amino]-pyridin-2-yl}-pyrrolidin-1-yl)-2-oxo-ethylcarbamoyl]-ethyl}-methyl-carbamicacid tert-butyl ester (300 mg, 0.50 mmol) in CH₂Cl₂ (1 mL) at −20° C. isadded TFA (5 ML, pre-cooled to −20° C.) slowly. After stirring at 0° C.for 30 min, the reaction mixture is concentrated and purified by prepHPLC (Column: Waters Sunfire prep C18 30×100 mm; Mobile phase: isocraticcondition, CH₃CN 28%/H₂O 72% with 0.1% TFA; Flow rate: 45 mL/min) togive(S)—N—[(S)-1-Cyclohexyl-2-((S)-2-{6-[(2-fluoro-phenyl)-methyl-amino]-pyridin-2-yl}-pyrrolidin-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide(206 mg, 67.0%) as white solid TFA salt. (HR Mass M/Z=496.3069 [M+1]).

In order to measure the ability of the inventive compounds to bind theBIR3 peptide binding pocket an ELISA and a cell based assays areutilized.

Elisa

Compounds are incubated with GST-BIR3 fusion protein and biotinylatedSMAC peptide (AVPFAQK) in stretavidin-coated 96 well plates. For XIAPBIR3 Smac Elisa, a GST-BIR3 fusion containing amino acids 248-358 fromXIAP is used. For CIAP1 BIR3 Smac Elisa, a GST-BIR3 fusion containingamino acids 259-364 from CIAP1 is used. Following a 30 minuteincubation, wells are extensively washed. The remaining GST-BIR3 fusionprotein is monitored by ELISA assay involving first, incubation withgoat anti-GST antibodies followed by washing and incubation withalkaline phosphatase conjugated anti-goat antibodies. Signal isamplified using Attophos (Promega) and read with Cytoflour Ex 450 nm/40and Em 580 nm. IC₅₀s correspond to concentration of compound whichdisplaces half of GST-BIR3 signal. The IC₅₀ for non-biotinylated Smac is400 nM. The IC₅₀ values of compounds listed in Table 1 in the describedELISA assays ranged from 0.005-10 μM.

Cell Proliferation Assay

The ability of compounds to inhibit tumor cell growth in vitro ismonitored using the CellTiter 96® AQ_(ueous) Non-Radioactive CellProliferation Assay (Promega). This assay is composed of solutions of anovel tetrazolium compound[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt; MTS] and an electron coupling reagent (phenazinemethosulfate) PMS. MTS is bioreduced by cells into a formazan product,the absorbance of which is measured at 490 nm. The conversion of MTSinto the aqueous soluble formazan product is accomplished bydehydrogenase enzymes found in metabolically active cells. The quantityof formazan product as measured by the amount of 490 nm absorbance isdirectly proportional to the number of living cells in culture. The IC₅₀values of compounds listed in Table 1 in the described cell assaysranged from 0.005-50 μM.

Example 196 Tablets 1 Comprising Compounds of the Formula (I)

Tablets, comprising, as active ingredient, 50 mg of any one of thecompounds of formula (I) mentioned in the preceding Examples 9-194 ofthe following composition are prepared using routine methods:

Composition: Active Ingredient 50 mg Wheat starch 60 mg Lactose 50 mgColloidal silica  5 mg Talcum  9 mg Magnesium stearate  1 mg Total 175mg Manufacture: The active ingredient is combined with part of the wheatstarch, the lactose and the colloidal silica and the mixture pressedthrough a sieve. A further part of the wheat starch is mixed with the5-fold amount of water on a water bath to form a paste and the mixturemade first is kneaded with this paste until a weakly plastic mass isformed.

The dry granules are pressed through a sieve having a mesh size of 3 mm,mixed with a pre-sieved mixture (1 mm sieve) of the remaining cornstarch, magnesium stearate and talcum and compressed to form slightlybiconvex tablets.

Example 197 Tablets 2 Comprising Compounds of the Formula (I)

Tablets, comprising, as active ingredient, 100 mg of any one of thecompounds of formula (I) of Examples 9-194 are prepared with thefollowing composition, following standard procedures:

Composition: Active Ingredient 100 mg Crystalline lactose 240 mg Avicel 80 mg PVPPXL  20 mg Aerosil  2 mg Magnesium stearate  5 mg Total 447 mgManufacture: The active ingredient is mixed with the carrier materialsand compressed by means of a tabletting machine (Korsch EKO,Stempeldurchmesser 10 mm).

Example 198 Capsules

Capsules, comprising, as active ingredient, 100 mg of any one of thecompounds of formula (I) given in Examples 9-194, of the followingcomposition are prepared according to standard procedures:

Composition: Active Ingredient 100 mg Avicel 200 mg PVPPXL  15 mgAerosil  2 mg Magnesium stearate  1.5 mg Total 318.5 mg  

Manufacturing is done by mixing the components and filling them intohard gelatine capsules, size 1.

1. A compound according to formula I

wherein R₁ is H; C₁-C₄ alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl orC₃-C₁₀cycloalkyl which are unsubstituted or substituted; R₂ is H; C₁-C₄alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl or C₃-C₁₀cycloalkyl which areunsubstituted or substituted; R₃ is H; —CF₃; —C₂F₅; C₁-C₄ alkyl; C₁-C₄alkenyl; C₁-C₄ alkynyl; —CH₂-Z or R₂ and R₃ together with the nitrogenform a het ring; Z is H; —OH; F; Cl; —CH₃; —CF₃; —CH₂Cl; —CH₂F or—CH₂OH; R₄ is C₁-C₁₆ straight or branched alkyl; C₁-C₁₆ alkenyl; C₁-C₁₆alkynyl; or —C₃-C₁₀cycloalkyl; —(CH₂)₁₋₆-Z₁; —(CH₂)₀₋₆-aryl; and—(CH₂)₀₋₆-het; wherein alkyl, cycloalkyl and phenyl are unsubstituted orsubstituted; Z₁ is —N(R₈)—C(O)—C₁-C₁₀alkyl;—N(R₈)—C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —N(R₈)—C(O)—(CH₂)₀₋₆-phenyl;—N(R₈)—C(O)—(CH₂)₁₋₆-het; —C(O)—N(R₉)(R₁₀); —C(O)—O—C₁-C₁₀alkyl;—C(O)—O—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —C(O)—O—(CH₂)₀₋₆-phenyl;—C(O)—O—(CH₂)₁₋₆-het; —O—C(O)—C₁-C₁₀alkyl;—O—C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —O—C(O)—(CH₂)₀₋₆-phenyl;—O—C(O)—(CH₂)₁₋₆-het; wherein alkyl, cycloalkyl and phenyl areunsubstituted or substituted; het is a 5-7 membered heterocyclic ringcontaining 1-4 heteroatoms selected from N, O and S, or an 8-12 memberedfused ring system including at least one 5-7 membered heterocyclic ringcontaining 1, 2 or 3 heteroatoms selected from N, O, and S, whichheterocyclic ring or fused ring system is unsubstituted or substitutedon a carbon or nitrogen atom; R₈ is H; —CH₃; —CF₃; —CH₂OH or —CH₂Cl; R₉and R₁₀ are each independently H; C₁-C₄alkyl; C₃-C₇cycloalkyl;—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —(CH₂)₀₋₆-phenyl; wherein alkyl, cycloalkyland phenyl are unsubstituted or substituted, or R₉ and R₁₀ together withthe nitrogen form het; R₅ is H; C₁-C₁₀-alkyl; aryl; phenyl;C₃-C₇cycloalkyl; —(CH₂)₁₋₆—C₃-C₇cycloalkyl; —C₁-C₁₀alkyl-aryl;—(CH₂)₀₋₆—C₃-C₇cycloalkyl-(CH₂)₀₋₆-phenyl;—(CH₂)₀₋₄CH—((CH₂)₁₋₄-phenyl)₂; —(CH₂)₀₋₆—CH(phenyl)₂; -indanyl;—C(O)—C₁-C₁₀alkyl; —C(O)—(CH₂)₁₋₆—C₃-C₇-cycloalkyl;—C(O)—(CH₂)₀₋₆-phenyl; —(CH₂)₀₋₆—C(O)-phenyl; —(CH₂)₀₋₆-het;—C(O)—(CH₂)₁₋₆-het; or R₅ is a residue of an amino acid, wherein thealkyl, cycloalkyl, phenyl and aryl substituents are unsubstituted orsubstituted; U is as shown in structure II:

wherein n=0-5; X is —CH or N; Ra and Rb are independently an O, S, or Natom or C₀₋₈ alkyl wherein one or more of the carbon atoms in the alkylchain may be replaced by a heteroatom selected from O, S or N, and wherethe alkyl may be unsubstituted or substituted; Rd is selected from: (a)—Re-Q-(Rf)_(p)(Rg)_(q); or (b) Ar₁-D-Ar₂; Rc is H or Rc and Rd maytogether form a cycloalkyl or het; where if Rd and Rc form a cycloalkylor het, R₅ is attached to the formed ring at a C or N atom; p and q areindependently 0 or 1; Re is C₁₋₈ alkyl or alkylidene, and Re which maybe unsubstituted or substituted; Q is N, O, S, S(O), or S(O)₂; Ar₁ andAr₂ are substituted or unsubstituted aryl or het; Rf and Rg are eachindependently H; —C₁-C₁₀alkyl; C₁-C₁₀alkylaryl; —OH; —O—C₁-C₁₀alkyl;—(CH₂)₀₋₆—C₃-C₇cycloalkyl; —O—(CH₂)₀₋₆-aryl; phenyl; aryl;phenyl-phenyl; —(CH₂)₁₋₆-het; —O—(CH₂)₁₋₆-het; —OR₁₁; —C(O)—R₁₁;—C(O)—N(R₁₁)(R₁₂); —N(R₁₁)(R₁₂); —S—R₁₁; —S(O)—R₁₁; —S(O)₂—R₁₁;—S(O)₂—NR₁₁R₁₂; —NR₁₁—S(O)₂—R₁₂; S—C₁-C₁₀alkyl; aryl-C₁-C₄alkyl;het-C₁-C₄-alkyl wherein alkyl, cycloalkyl, het and aryl areunsubstituted or substituted; —SO₂—C₁-C₂alkyl; —SO₂—C₁-C₂alkylphenyl;—O—C₁-C₄alkyl; or R_(g) and R_(f) form a ring selected from het or aryl;D is —CO—; —C(O)—C₁₋₇ alkylene or arylene; —CF₂—; —O—; —S(O)_(r) where ris 0-2; 1,3dioaxolane; or C₁₋₇ alkyl-OH; where alkyl, alkylene orarylene may be unsubstituted or substituted with one or more halogens,OH, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃; or D is —N(Rh) wherein Rh isH; C₁₋₇ alkyl (unsub or substituted); aryl; —O(C₁₋₇cycloalkyl) (unsub orsubstituted); C(O)—C₁-C₁₀alkyl; C(O)—CO—C_(o)—C₁₀alkylaryl;C—O—C₁-C₁₀alkyl; C—O—C_(o)—C₁₀alkyl-aryl or SO₂—C₁-C₁₀-alkyl;SO₂—(C_(o)—C₁₀-alkylaryl); R₆, R₇, R′₆ and R′₇ are each independently H;—C₁-C₁₀ alkyl; —C₁-C₁₀ alkoxy; aryl-C₁-C₁₀ alkoxy; —OH; —O—C₁-C₁₀alkyl;—(CH₂)₀₋₆—C₃-C₇cycloalkyl; —O—(CH₂)₀₋₆-aryl; phenyl; —(CH₂)₁₋₆-het;—O—(CH₂)₁₋₆-het; —OR₁₁; —C(O)—R₁₁; —C(O)—N(R₁₁)(R₁₂); —N(R₁₁)(R₁₂);—S—R₁₁; —S(O)—R₁₁; —S(O)₂—R₁₁; —S(O)₂—NR₁₁R₁₂; —NR₁₁—S(O)₂—R₁₂; whereinalkyl, cycloalkyl and aryl are unsubstituted or substituted; and R₆, R₇,R′₆ and R′₇ can be united to form a ring system; R₁₁ and R₁₂ areindependently H; C₁-C₁₀ alkyl; —(CH₂)₀₋₆—C₃-C₇cycloalkyl;—(CH₂)₀₋₆—(CH)₀₋₁(aryl)₁₋₂; —C(O)—C₁-C₁₀alkyl;—C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —C(O)—O—(CH₂)₀₋₆-aryl;—C(O)—(CH₂)₀₋₆—O-fluorenyl; —C(O)—NH—(CH₂)₀₋₆-aryl; —C(O)—(CH₂)₀₋₆-aryl;—C(O)—(CH₂)₁₋₆-het; —C(S)—C₁-C₁₀alkyl; —C(S)—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—C(S)—O—(CH₂)₀₋₆-aryl; —C(S)—(CH₂)₀₋₆—O-fluorenyl;—C(S)—NH—(CH₂)₀₋₆-aryl; —C(S)—(CH₂)₀₋₆-aryl; —C(S)—(CH₂)₁₋₆-het; whereinalkyl, cycloalkyl and aryl are unsubstituted or substituted; or R₁₁ andR₁₂ are a substituent that facilitates transport of the molecule acrossa cell membrane; or R₁₁ and R₁₂ together with the nitrogen atom formhet; wherein the alkyl substituents of R₁₁ and R₁₂ may be unsubstitutedor substituted by one or more substituents selected from C₁-C₁₀alkyl,halogen, OH, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃; substitutedcycloalkyl substituents of R₁₁ and R₁₂ are substituted by one or moresubstituents selected from a C₁-C₁₀ alkene; C₁-C₆alkyl; halogen; OH;—O—C₁-C₆alkyl; —S—C₁-C₆alkyl or —CF₃; and substituted phenyl or aryl ofR₁₁ and R₁₂ are substituted by one or more substituents selected fromhalogen; hydroxy; C₁-C₄ alkyl; C₁-C₄ alkoxy; nitro; —CN;—O—C(O)—C₁-C₄alkyl and —C(O)—O—C₁-C₄-aryl, or pharmaceuticallyacceptable salts thereof.
 2. A compound formula (I) according to claim 1wherein R₁ is H; —C₁-C₄ alkyl; —C₁-C₄ alkenyl; —C₁-C₄ alkynyl orcycloalkyl which are unsubstituted or substituted by one or moresubstituents selected from halogen, —OH, —SH, —OCH₃, —SCH₃, —CN, —SCNand nitro; R₂ is H; —C₁-C₄alkyl; —C₁-C₄ alkenyl; —C₁-C₄ alkynyl orcycloalkyl which are unsubstituted or substituted by one or moresubstituents selected from halogen, —OH, —SH, —OCH₃, —SCH₃, —CN, —SCNand nitro; R₃ is H; —CF₃; —C₂F₅; —C₁-C₄alkyl; —C₁-C₄alkenyl;—C₁-C₄alkynyl; —CH₂-Z or R₂ and R₃ together with the nitrogen form ahet; Z is H; —OH; F; Cl; —CH₃; —CF₃; —CH₂Cl; —CH₂F or —CH₂OH; R₄ isC₁-C₁₆ straight or branched alkyl; C₁-C₁₆ alkenyl; C₁-C₁₆ alkynyl; orcycloalkyl; —(CH₂)₁₋₆-Z₁; —(CH₂)₀₋₆-phenyl; and —(CH₂)₀₋₆-het; whereinalkyl, cycloalkyl and phenyl are unsubstituted or substituted; Z₁ is—N(R₈)—C(O)—C₁-C₁₀alkyl; —N(R₈)—C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—N(R₈)—C(O)—(CH₂)₀₋₆-phenyl; —N(R₈)—C(O)—(CH₂)₁₋₆-het; —C(O)—N(R₉)(R₁₀);—C(O)—O—C₁-C₁₀alkyl; —C(O)—O—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—C(O)—O—(CH₂)₀₋₆-phenyl; —C(O)—O—(CH₂)₁₋₆-het; —O—C(O)—C₁-C₁₀ alkyl;—O—C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —O—C(O)—(CH₂)₀₋₆-phenyl;—O—C(O)—(CH₂)₁₋₆-het, wherein alkyl, cycloalkyl and phenyl areunsubstituted or substituted; het is a 5-7 membered heterocyclic ringcontaining 1-4 heteroatoms selected from N, O and S, or an 8-12 memberedfused ring system including at least one 5-7 membered heterocyclic ringcontaining 1, 2 or 3 heteroatoms selected from N, O, and S, whichheterocyclic ring or fused ring system is unsubstituted or substitutedon a carbon atom by halogen, hydroxy, C₁-C₄alkyl, C₁-C₄ alkoxy, nitro,—O—C(O)—C₁-C₄alkyl or —C(O)—O—C₁-C₄-alkyl or on a nitrogen by C₁-C₄alkyl, —O—C(O)—C₁-C₄alkyl or —C(O)—O—C₁-C₄alkyl; R₈ is H, —CH₃, —CF₃,—CH₂OH or —CH₂Cl; R₉ and R₁₀ are each independently H; —C₁-C₄alkyl;C₃-C₇cycloalkyl; —(CH₂)₁₋₆—C₃-C₇cycloalkyl; —(CH₂)₀₋₆-phenyl; whereinalkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R₉ andR₁₀ together with the nitrogen form het; R₅ is H; C₁-C₁₀alkyl;C₃-C₇cycloalkyl; —(CH₂)₁₋₆—C₃-C₇cycloalkyl; —C₁-C₁₀alkyl-aryl;—(CH₂)₀₋₆—C₃-C₇cycloalkyl-(CH₂)₀₋₆-phenyl;—(CH₂)₀₋₄CH—((CH₂)₁₋₄-phenyl)₂; —(CH₂)₀₋₆—CH(phenyl)₂; -indanyl;—C(O)—C₁-C₁₀alkyl; —C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—C(O)—(CH₂)₀₋₆-phenyl; —(CH₂)₀₋₆-het; —C(O)—(CH₂)₁₋₆-het; or R₅ is aresidue of an amino acid, wherein alkyl, cycloalkyl, phenyl and aryl areunsubstituted or substituted; U is a as shown in structure II:

wherein n=0-5; X is —CH or N; Ra and Rb are independently an O, S, or Natom or C₀₋₈ alkyl wherein one or more of the carbon atoms in the alkylchain may be replaced by a heteroatom selected from O, S or N, and wherethe alkyl may be unsubstituted or substituted; Rd is selected from: (a)Re-Q-(Rf)_(p)(Rg)_(q); or (b) Ar₁-D-Ar₂; p and q are independently 0 or1; Rc is H or Rd and Rc together form cycloalkyl or het; where if Rd andRc form a cycloalkyl or heteroring, R₅ is attached to the formed ring ata C or N atom; Re is C₁₋₈ alkyl which may be unsubstituted orsubstituted; Q is N, O, S, S(O), or S(O)₂; Ar₁ and Ar₂ are substitutedor unsubstituted aryl or het; Rf and Rg are each independently H orsubstituted or unsubstituted C₀-C₁₀alkyl, or C₁-C₁₀alkylaryl; D is —CO—;—C(O)—C₁₋₇ alkylene or arylene; —CF₂—; —O—; —S(O)_(r) where r is 0-2;1,3dioaxolane; or C₁₋₇ alkyl-OH; where alkyl, alkylene or arylene may beunsubstituted or substituted with one or more halogens, OH,—O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃; or D is —N(Rh) wherein Rh is H;C₁₋₇ alkyl (unsub or substituted); aryl; —O(C₁₋₇cycloalkyl) (unsub orsubstituted); C(O)—C₁-C₁₀alkyl; C(O)—C_(o)-C₁₀alkylaryl;C—O—C₁-C₁₀alkyl; C—O—C_(o)—C₁₀alkyl-aryl or SO₂—C₁-C₁₀-alkyl;SO₂—(C_(o)—C₁₀-alkylaryl); and R₆, R₇, R′₆ and R′₇ are eachindependently H; —C₁-C₁₀ alkyl; —OH; —O—C₁-C₁₀alkyl;—(CH₂)₀₋₆—C₃-C₇cycloalkyl; —O—(CH₂)₀₋₆-aryl; phenyl; —(CH₂)₁₋₆-het;—O—(CH₂)₁₋₆-het; —OR₁₁; —C(O)—R₁₁; —C(O)—N(R₁₁)(R₁₂); —N(R₁₁)(R₁₂);—S—R₁₁; —S(O)—R₁₁; —S(O)₂—R₁₁; —S(O)₂—NR₁₁R₁₂; —NR₁₁—S(O)₂—R₁₂; whereinalkyl, cycloalkyl and aryl are unsubstituted or substituted; or any R₆,R₇, R′₆ and R′₇ can be united to form a ring system; R₁₁ and R₁₂ areindependently H; C₁-C₁₀ alkyl; —(CH₂)₀₋₆—C₃-C₇cycloalkyl;—(CH₂)₀₋₆—(CH)₀₋₁(aryl)₁₋₂; —C(O)—C₁-C₁₀alkyl;—C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl; —C(O)—O—(CH₂)₀₋₆-aryl;—C(O)—(CH₂)₀₋₆—O-fluorenyl; —C(O)—NH—(CH₂)₀₋₆-aryl; —C(O)—(CH₂)₀₋₆-aryl;—C(O)—(CH₂)₁₋₆-het; —C(S)—C₁-C₁₀alkyl; —C(S)—(CH₂)₁₋₆—C₃-C₇cycloalkyl;—C(S)—O—(CH₂)₀₋₆-aryl; —C(S)—(CH₂)₀₋₆—O-fluorenyl;—C(S)—NH—(CH₂)₀₋₆-aryl; —C(S)—(CH₂)₀₋₆-aryl; —C(S)—(CH₂)₁₋₆-het, whereinalkyl, cycloalkyl and aryl are unsubstituted or substituted; or R₁₁ andR₁₂ are a substituent that facilitates transport of the molecule acrossa cell membrane; or R₁₁ and R₁₂ together with the nitrogen are het; arylof R₁₁ and R₁₂ can be phenyl, naphthyl, or indanyl which isunsubstituted or substituted; alkyl of R₁₁ and R₁₂ may be unsubstitutedor substituted by one or more substituents selected from a C₁-C₁₀alkene, halogen, OH, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl and —CF₃; cycloalkylof R₁₁ and R₁₂ may be unsubstituted or substituted by one or moreselected from a C₁-C₁₀ alkene, one or more halogens, C₁-C₆alkyl,halogen, OH, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃; and phenyl or aryl ofR₁ and R₁₂ may be unsubstituted or substituted by one or moresubstituents selected from halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy,nitro, —CN, —O—C(O)—C₁-C₄alkyl and —C(O)—O—C₁-C₄-aryl; orpharmaceutically acceptable salts thereof.
 3. A compound according toclaim 1 wherein R₁ and R₂ are independently H or substituted orunsubstituted C₁-C₄alkyl; R₄ is C₁-C₁₆ straight or branched alkyl, orC₃-C₁₀cycloalkyl, wherein the alkyl or cycloalkyl may be unsubstitutedor substituted; R₅ is H; C₁-C₁₀alkyl; C₁-C₁₀alkyl-aryl;—C(O)—(CH₂)₀₋₆-Phenyl; —(CH₂)₀₋₆—C(O)-Phenyl; aryl; indanyl; naphthyl orR₅ is a residue of an amino acid, wherein the alkyl or aryl substituentsare unsubstituted or substituted; U is as shown in structure II:

wherein n=0-5; X is —CH or N; Ra and Rb are independently an O, S, or Natom or C₀₋₈ alkyl wherein one or more of the carbon atoms in the alkylchain may be replaced by a heteroatom selected from O, S or N, and wherethe alkyl may be unsubstituted or substituted; Rd is selected from (a)—Re-Q-(Rf)_(p)(Rg)_(q); or (c) Ar₁-D-Ar₂; Rc is H or Rc and Rd togetherform cycloalkyl or het; where if Rd and Rc form a cycloalkyl orheteroring, R₅ is attached to the formed ring at a C or N atom; p and qare independently 0 or 1; Re is C₁₋₈ alkyl, or methylidene which may beunsubstituted or substituted; Q is N, O, S, S(O), or S(O)₂; Ar₁ and Ar₂are substituted or unsubstituted aryl or het; Rf and Rg are eachindependently H or substituted or unsubstituted C₀-C₁₀alkyl;C₁-C₁₀alkylaryl; aryl-C₁-C₁₀alkyl; het-C₁-C₁₀alkyl—C(O)—C₁-C₄-alkyl-phenyl; —C(O)—C₁-C₄-alkyl; —SO₂—C₁-C₂alkyl;—SO₂—C₁-C₂alkylphenyl; —O—C₁-C₄-alkyl; D is —C(O)—; C₁₋₇ alkylene orarylene; —O—, or —S(O)_(r) where r is 0-2; where alkyl, alkylene orarylene which may be unsubstituted or substituted with one or morehalogens; —OH; —O—C₁-C₆alkyl; —S—C₁-C₆alkyl or —CF₃; or D is NRh whereinRh is H; C₁₋₇ alkyl (unsubstituted or substituted); aryl; —OC₁₋₇cycloalkyl (unsubstituted or substituted); —CO—C₀₋₁₀ alkyl or aryl orSO₂—C₀₋₁₀-alkyl or aryl; and R₆, R₇, R′₆ and R′₇ are each independentlyH, —C₁-C₁₀ alkyl, or —OH, alkoxy, or aryloxy; or pharmaceuticallyacceptable salts thereof.
 4. A compound according to claim 1 wherein Uis a bicyclic saturated or unsaturated ring system, consisting of allcarbon skeleton or with one or more heteroatoms such as O, N, S butpreferably as shown in structure III:

wherein wherein any of the ring carbon atoms can be unsubstituted orsubstituted with any of the substituted defined above for R₆, R₇, R_(6′)and R₇′; X is CH or N; V is O, F₂, Cl₂, Br₂, I₂, S, YH, H₂, NH, or C₁-C₄alkyl; W is —CH, or —N; n is 0-3; and m is 0-3.
 5. A compound accordingto claim 1 wherein the ring carbon atoms on U are substituted withsubsituents independently selected from halo, H, OH, lower alkyl orlower alkoxy, wherein alkyl or alkoxy are unsubstituted or substitutedby halogen, OH, lower alkyl or lower alkoxy.
 6. A compound according toclaim 1 wherein R₁ and R₃ are preferably methyl or ethyl; R₂ isespecially H methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl; R₄ is —C₁-C₄alkyl; —C₃-C₇ cycloalkyl;—(CH₂)₁₋₆-cycloalkyl; or —(CH₂)₀₋₆aryl; R₅ is —C₁-C₄alkyl-phenyl;—C(O)—C₁-C₄-alkyl-phenyl; —C₁-C₄—C(O)-alkyl-pheny or aryl, R₅ isparticularly phenylmethyl, phenylethyl and phenylpropyl; indanyl,naphthyl; —C(O)—CH₂-phenyl or —CH₂—C(O)-phenyl; R₆ and R₇ are H ormethyl; U has the structure of formula III:

wherein wherein any of the ring carbon atoms can be unsubstituted orsubstituted with any of the substituted defined above for R₆, R₇, R_(6′)and R₇′; X is N; V is O or H₂; W is —N; n is 1; and m is 1 or
 2. 7. Acompound according to claim 1 wherein R₁ and R₃ are preferably methyl orethyl; R₂ is H; R₄ is C₁-C₄alkyl; C₃-C₇ cycloalkyl; C₁-C₇cycloalkyl-C₁-C₇alkyl; phenyl-C₁-C₇alkyl or aryl. R₄ is particularlymethyl, ethyl, butyl, isopropyl, t-butyl, or cyclohexyl;—CH₂-cyclopentyl, —CH₂-cyclohexyl; —CH₂-cyclopropyl; phenyl or—CH₂-phenyl; R₅ is —C₁-C₄-alkyl-phenyl; —C(O)—C₁-C₄-alkyl-phenyl;—C₁-C₄—C(O)-alkyl-pheny or aryl. R₅ is particularly phenylethyl;indanyl, naphthyl; —C(O)—CH₂-phenyl; —CH₂—C(O)-phenyl; or(CF₃O)phenylethyl; R₆, R′₆, R₇ and R′₇ are H; U has the structure offormula III wherein wherein any of the ring carbon atoms can beunsubstituted or substituted with any of the substituted defined abovefor R₆, R₇, R_(6′) and R₇′; X is N; V is O or H₂; W is —N; n is 1; and mis 1 or
 2. 8. A compound according to claim 1 wherein R₁ and R₃ arepreferably methyl or ethyl; R₂ is especially H, methyl, ethyl,chloromethyl, dichloromethyl or trifluoromethyl; R₄ is C₁-C₄alkyl orC₃-C₇ cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, orcyclohexyl; R₅ is H; U has the structure of formula II wherein X is N;R₆, R′₆, R₇, and R′₇ are H; n is O; Rc is H; Ar₁ and Ar₂ are substitutedor unsubstituted phenyl or het particularly tetrazolyl, 1, 2,3-triazole,pyrazole, oxazole, pyrrolyl, triazine, pyrimidine, imidazol, oxadiazol;and and D is C₁ alkyl which may optionally be substituted with halo,especially F.
 9. A compound according to claim 1 wherein R₁ and R₃ arepreferably methyl or ethyl; R₂ is especially H, methyl, ethyl,chloromethyl, dichloromethyl or trifluoromethyl; R₄ is C₁-C₄alkyl; C₃-C₇cycloalkyl; C₁-C₇ cycloalkyl-C₁-C₇alkyl; phenyl-C₁-C₇alkyl or aryl; R₅is H; U has the structure of formula II wherein X is N; R₆, R′₆, R₇, andR′₇ are H; or R₆ is —C(O)—C₁-C₄-alkyl-phenyl and R′₆, R₇, and R′₇ are H;n is O; Rc is H; Ar₁ and Ar₂ are substituted or unsubstituted phenyl orhet, particularly triazine, pyrimidine, pyridine, oxazole,2,4-difluorophenyl, Cl-phenyl or fluorophenyl; and D is N(Rh), where Rhis H, Me, —CHO, —SO₂, —C(O), —CHOH, CF₃ or —SO₂CH₃.
 10. A compoundaccording to claim 1 wherein R₁ and R₃ are preferably methyl or ethyl;R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl; R₄ is C₁-C₄alkyl; C₃-C₇ cycloalkyl; C₁-C₇cycloalkyl-C₁-C₇alkyl; phenyl-C₁-C₇alkyl or aryl. R₄ is particularlymethyl, ethyl, butyl, isopropyl, t-butyl, or cyclohexyl;—CH₂-cyclopentyl, —CH₂-cyclohexyl; —CH₂-cyclopropyl; phenyl or—CH₂-phenyl; R₅ is H; U has the structure of formula II wherein X is N;R₆, R′₆, R₇, and R′₇ are H; n is O; Re is H; Ar₁ and Ar₂ are substitutedor unsubstituted phenyl or het particularly pyrimidine, pyridine,oxazole, 2-methyloxazole; and D is —O—.
 11. A compound according toclaim 1 wherein R₁ and R₃ are preferably methyl or ethyl; R₂ isespecially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl; R₄ is C₁-C₄alkyl or C₃-C₇ cycloalkyl particularlyisopropyl, t-butyl, cyclopentyl, or cyclohexyl; R₅ is H; U has thestructure of formula II wherein X is N; R₆, R′₆, R₇, and R′₇ are H; n isO; Rc is H; Ar₁ and Ar₂ are substituted or unsubstituted phenyl or het;and D is S, S(O), or S(O)₂.
 12. A compound according to claim 1 whereinR₁ and R₃ are preferably methyl or ethyl; R₂ is especially H, methyl,ethyl, chloromethyl, dichloromethyl or trifluoromethyl; R₄ is C₁-C₄alkylor C₃-C₇ cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, orcyclohexyl; R₅ is H; U has the structure of formula II wherein X is N;R₆, R′₆, R₇, and R′₇ are H; n is O; Rc is H; Ar₁ and Ar₂ are substitutedor unsubstituted phenyl or het, particularly oxazole, thaizole andozadiazole; and D is C(O), or 1,3-dioxolane.
 13. A compound according toclaim 1 wherein R₁ and R₃ are preferably methyl or ethyl; R₂ isespecially H, methyl, ethyl, chloromethyl, dichloromethyl ortrifluoromethyl; R₄ is C₁-C₄alkyl or C₃-C₇ cycloalkyl particularlyisopropyl, t-butyl, cyclopentyl, or cyclohexyl; R₅ is H or phenyl C₁-C₁₀alkyl such as phenylethyl; U has the structure of formula II wherein Xis N; R₆, R′₆, R₇, and R′₇ are H; n is O; Rc and Rd are het,particularly pyrrolidine; pyrrolidin-2-one; or pyrrolidin-3-one.
 14. Acompound according to claim 1 wherein R₁ and R₃ are preferably methyl orethyl; R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethylor trifluoromethyl; R₄ is C₁-C₄alkyl or C₃-C₇ cycloalkyl particularlyisopropyl, t-butyl, cyclopentyl, or cyclohexyl; R₅ is H, indanyl orphenyl; U has the structure of formula II wherein X is N; Q is O; R₆,R′₆, R₇, and R′₇ are H; n is O; Re is C₁ alkyl; and p and q are
 0. 15. Acompound according to claim 1 wherein R₁ and R₃ are preferably methyl orethyl; R₂ is especially H, methyl, ethyl, chloromethyl, dichloromethylor trifluoromethyl; R₄ is C₁-C₄alkyl or C₃-C₇ cycloalkyl particularlyisopropyl, t-butyl, cyclopentyl, or cyclohexyl; R₅ is H, indanyl orphenyl; U has the structure of formula II wherein X is N; Q is N; R₆,R′₆, R₇, and R′₇ are H; n is O; Re is C₁ alkyl; and R_(g) is H, C₁-C₈alkyl, methyl, ethyl, hexyl, heptyl, octyl, or CH₂CF₃, or aryl-C₁-C₄alkyl particularly phenylethyl, furanylethyl; C₃-C₇ cycloalkylparticularly cyclohexyl; ethylphenyl; —C(O)—C₁-C₄-alkyl-phenyl;—C(O)—C₁-C₄-alkyl; —C₁-C₄-alkyl-aryl particularly —CH₂-phenyl;—CH₂-thiophene, —CH₂-furan, —CH₂-pyrrolidinyl, —CH₂-imidazole,—CH₂-triazole, —CH₂-imidazole; and R_(f) is C₁-C₂ alkyl; C₁-C₂alkylphenyl; —SO₂—C₁-C₂alkyl; —SO₂—C₁-C₂alkylphenyl; —O—C₁-C₄-alkylparticularly O-ethyl; phenyl-phenyl, 1,2,3,4tetrahydronapthalene andindanyl.
 16. A compound according to claim 1 wherein R₁ and R₃ arepreferably methyl or ethyl; R₂ is especially H, methyl, ethyl,chloromethyl, dichloromethyl or trifluoromethyl; R₄ is C₁-C₄alkyl orC₃-C₇ cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, orcyclohexyl; R₅ is H, indanyl or phenyl; U has the structure of formulaII wherein X is N; Q is N; R₆, R′₆, R₇, and R′₇ are H; n is O; Re is C₁alkyl; and R_(g) and R_(f) form a ring selected from het or arylparticularly 2,3,4,5-tetrahydrobenzo[c]azepine; 1,2,3,4tetrahydroquinoline; indanyl which may be substituted withC₁-C₄alkylphenyl
 17. A compound according to claim 1 wherein R₁ and R₃are preferably methyl or ethyl; R₂ is especially H, methyl, ethyl,chloromethyl, dichloromethyl or trifluoromethyl; R₄ is C₁-C₄alkyl orC₃-C₇ cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, orcyclohexyl; R₅ is phenyl; U has the structure of formula II wherein X isN; Q is O, S, S(O) or S(O)₂; R₆, R′₆, R₇, and R′₇ are H; n is O; Re isC₁ alkyl; q is 0; Rc is H; and R_(f) is C₂ alkyl.
 18. A compoundaccording to claim 1 wherein R₃ and R₄ have the stereochemistryindicated in formula IV, with the definitions of the variablesubstituents and preferences described herein above also applying tocompounds having the stereochemistry indicated in formula IV.


19. A compound according to claim 18 wherein compound with thestereochemistry of formula (IV) wherein R₁ and R₃ are preferably methylor ethyl; R₂ is H, methyl, ethyl, or substituted methyl especiallychloromethyl, dichloromethyl and trifluoromethyl; preferably R₂ is H orunsubstituted methyl; R₄ is C₁-C₄alkyl or C₃-C₇ cycloalkyl particularlyisopropyl, t-butyl, cyclopentyl, or cyclohexyl; R₅ is—C₁-C₄-alkyl-phenyl, particularly phenylmethyl, phenylethyl andphenylpropyl, indanyl, naphthyl; and R₆ and R₇ are H or methyl.
 20. Acompound according to claim 1 wherein the stereochemistry for U is asshown in Figure V


21. A pharmaceutical composition which comprises a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundof formula I according to claim
 1. 22. A method of treating aproliferative disease which comprises administering a therapeuticallyeffective amount of a compound of formula I according to claim 1 to amammal in need of such treatment.
 23. A method of claim 22 wherein themammal is a human.
 24. A compound selected from:N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-acetamide;2-Methylamino-N-[2-methyl-1-(7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-propionamide;2-Methylamino-N-[2-methyl-1-(7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-propionamide;2-Methylamino-N-[2-methyl-1-(8-oxo-7-phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carbonyl)-propyl]-propionamide;2-Methylamino-N-[2-methyl-1-(7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-butyramide;2-Methylamino-N-[2-methyl-1-(7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-butyramide;2-Methylamino-N-[2-methyl-1-(8-oxo-7-phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carbonyl)-propyl]-butyramide;N-[1-Cyclohexyl-2-oxo-2-(7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide;2-Methylamino-N-{2-methyl-1-[5-(3-methyl-hexa-3,5-dienyl)-6-oxo-hexahydro-pyrrolo[3,4-b]pyrrole-1-carbonyl]-propyl}-propionamide;2-Methylamino-N-[2-methyl-1-(3-methyl-7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-propionamide;2-Methylamino-N-[2-methyl-1-(3-methyl-7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-propionamide;N-[1-(4-Benzyloxy-7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-2-methyl-propyl]-2-methylamino-propionamide;N-[1-Cyclohexyl-2-oxo-2-(8-oxo-7-phenethyl-octahydro-pyrrolo[2,3-c]azepin-1-yl)-ethyl]-2-methylamino-butyramide;N-[1-Cyclohexyl-2-oxo-2-(8-oxo-7-phenethyl-octahydro-pyrrolo[2,3-c]azepin-1-yl)-ethyl]-2-methylamino-butyramide;N-[1-Cyclohexyl-2-oxo-2-(7-phenethyl-octahydro-pyrrolo[2,3-c]azepin-1-yl)-ethyl]-2-methylamino-propionamide;2-Methylamino-N-[2-methyl-1-(8-oxo-7-phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carbonyl)-propyl]-butyramide;(S)—N-{(S)-2-[(R)-2-(3-Benzyl-phenyl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;(S)—N-{(S)-2-[(S)-2-(3-Benzyl-phenyl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;(S)-2-Methylamino-N—((S)-2-methyl-1-{(S)-2-[3-(methyl-phenyl-amino)-phenyl]-pyrrolidine-1-carbonyl}-propyl)-propionamide;(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[3-(methyl-phenyl-amino)-phenyl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;(S)—N—((S)-1-Cyclohexyl-2-{(R)-2-[3-(methyl-phenyl-amino)-phenyl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;(S)—N-{(S)-1-Cyclohexyl-2-oxo-2-[(R)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethyl}-2-methylamino-propionamide;(S)—N-{(S)-1-Cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethyl}-2-methylamino-propionamide;(S)—N-{(S)-1-Cyclohexyl-2-oxo-2-[(R)-2-(3-phenylsulfanyl-phenyl)-pyrrolidin-1-yl]-ethyl}-2-methylamino-propionamide;(S)—N-{(S)-1-Cyclohexyl-2-oxo-2-[(S)-2-(3-phenylsulfanyl-phenyl)-pyrrolidin-1-yl]-ethyl}-2-methylamino-propionamide;(S)—N-{(S)-2-[(R)-2-(3-Benzenesulfonyl-phenyl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;(S)—N-{(S)-2-[(S)-2-(2-Benzyl-2H-tetrazol-5-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;(S)—N-{(S)-2-[(S)-2-(2-Benzyl-2H-tetrazol-5-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-butyramide;(S)—N-{(S)-2-[(S)-2-(1-Benzyl-1H-tetrazol-5-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;(S)—N-{(S)-2-[(S)-2-(1-Benzyl-1H-tetrazol-5-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-butyramide;(S)—N-{(S)-2-[2-(Benzyloxyimino-hyl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;(S)-2-Methylamino-N-{(S)-2-methyl-1-[2-((S)-phenylmethanesulfonylamino-methyl)-pyrrolidine-1-carbonyl]-propyl}-propionamide;(S)-2-Methylamino-N-{(S)-2-methyl-1-[2-((S)-phenylmethanesulfonylamino-methyl)-pyrrolidine-1-carbonyl]-propyl}-butyramide;N-(1-Cyclohexyl-2-{(S)-2-[(ethyl-indan-2-yl-amino)-methyl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-((S)-methylamino)-propionamide;(S)—N—[(S)-1-Cyclohexyl-2-(2-{[(S)-indan-2-yl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-pyrrolidin-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide;(S)—N—((S)-1-Cyclohexyl-2-{2-[((S)-cyclohexyl-phenethyl-amino)-methyl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;(S)—N—((S)-2-{2-[((S)-tert-Butyl-phenethyl-amino)-methyl]-pyrrolidin-1-yl}-1-cyclohexyl-2-oxo-ethyl)-2-methylamino-propionamide;(S)—N—((S)-1-Cyclohexyl-2-{2-[((S)—furan-2-ylmethyl-phenethyl-amino)-methyl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;(S)—N—[(S)-1-Cyclohexyl-2-oxo-2-(2-{[(S)-phenethyl-(4-phenyl-butyl)-amino]-methyl}-pyrrolidin-1-yl)-ethyl]-2-methylamino-propionamide;(S)—N—[(S)-1-Cyclohexyl-2-(2-{[(S)—methyl-(4-phenyl-butyl)-amino]-methyl}-pyrrolidin-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide;N—[(S)-1-(S)-Cyclohexyl-2-oxo-2-((R)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-acetamide;(S)—N—[(S)-1-(S)-Cyclohexyl-2-oxo-2-((R)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-butyramide;(S)-2-Methylamino-N—[(S)-2-methyl-1-((R)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-propionamide;(S)—N—[(S)-2,2-Dimethyl-1-((R)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-2-methylamino-propionamide;(S)-2-Methylamino-N—[(S)-2-methyl-1-((R)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-butyramide;(S)—N—[(S)-2,2-Dimethyl-1-((3aR,7aS)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-2-methylamino-propionamide;(S)—N—((S)-1-Cyclohexyl-2-oxo-2-{(3aR,7aS)-6-[2-(2-trifluoromethoxy-phenyl)-ethyl]-octahydro-pyrrolo[2,3-c]pyridin-1-yl}-ethyl)-2-methylamino-propionamide;(S)—N—((S)-1-Cyclohexyl-2-oxo-2-{(3aR,7aS)-6-[2-(3-trifluoromethoxy-phenyl)-ethyl]-octahydro-pyrrolo[2,3-c]pyridin-1-yl}-ethyl)-2-methylamino-propionamide;(S)—N—[(S)-1-Cyclohexyl-2-oxo-2-((3aR,6aR)-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-butyramide;(S)—N—[(S)-1-Cyclohexyl-2-oxo-2-((3aS,6aS)-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-butyramide;(S)—N—[(S)-1-Cyclohexyl-2-oxo-2-((3aS,6aS)-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-propionamide;(S)—N—[(S)-1-Cyclohexyl-2-oxo-2-((3aS,6aS)-6-oxo-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-butyramide;(S)—N—[(R)-1-Cyclohexyl-2-oxo-2-((3aS,6aS)-6-oxo-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-butyramide;(S)—N—[(S)-1-Cyclohexyl-2-oxo-2-((3aS,6aS)-6-oxo-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-propionamide;(S)—N—[(R)-1-Cyclohexyl-2-oxo-2-((3aS,6aS)-6-oxo-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-propionamide;(S)—N—[(S)-1-(R)-Cyclohexyl-2-oxo-2-((S)-7-phenethyl-octahydro-pyrrolo[2,3-c]azepin-1-yl)-ethyl]-2-methylamino-propionamide;(S)—N—[(S)-1-(S)-Cyclohexyl-2-oxo-2-((R)-8-oxo-7-phenethyl-octahydro-pyrrolo[2,3-c]azepin-1-yl)-ethyl]-2-methylamino-butyramide;and pharmaceutically acceptable salts thereof.
 25. A compound selectedfromN-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide;N-{1-cyclohexyl-2-oxo-2-(2-(3-phenoxy-phenyl)pyrrolidin-1-yl]-ethyl}-2-methylaminopropionamide;N-[1-cyclohexyl-2-oxo-2-(7-phenethyl-octahydro-pyrrolo[2,3-c]azepin-1-yl)-ethyl]-2-methylaminopropionamide;(S)—N—((S)-1-Cyclohexyl-2-{(2S,3R)-2-[(ethyl-phenethyl-amino)-methyl]-3-methyl-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;N-{2-[2-(2-benzyl-2H-tetrazol-5-yl)-pyrrolidin-1-yl]-cyclohexyl-2-oxo-ethyl}-2-methylamino-butyramide;N-{2-[2-Benxyloxyimino-methyl)-pyrrolidin-1-yl}-1-cyclohexyl-2-oxo-ethyl-2-methylamino-propionamide;and pharmaceutically acceptable salts thereof.
 26. A compound selectedfrom(S)—N-{(S)-1-Cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethyl}-2-methylamino-propionamide;(S)—N-{(S)-1-Cyclohexyl-2-oxo-2-[(S)-2-(3-phenylsulfanyl-phenyl)-pyrrolidin-1-yl]-ethyl}-2-methylamino-propionamide;(S)—N-{(S)-2-[(S)-2-(2-Benzyl-2H-tetrazol-5-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;(S)—N-{(S)-2-[(S)-2-(2-Benzyl-2H-tetrazol-5-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-butyramide;(S)—N-{(S)-2-[(S)-2-(1-Benzyl-1H-tetrazol-5-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;(S)—N-{(S)-2-[(S)-2-(1-Benzyl-1H-tetrazol-5-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-butyramide;and pharmaceutically acceptable salts thereof